Note: Descriptions are shown in the official language in which they were submitted.
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~ ~ nlcl~BSTT1'UTED-4-AMINOPYRID~f2 3-Dll'YRIMIDINE COMPOUNDS
Technical Field
The present invention relates a method for inhibiting adenosine kinase by
administering 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds, to
pharmaceutical compositions containing such compounds, as well as novel 6,7-
disubstituted-4-aminopyrido[2,3-d]pyrimidine compounds.
Backeround O~T'JZe Invention
Adenosine kinase (ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) is a
ubiquitous enzyme which catalyzes the phosphorylation of adenosine to AMP,
using ATP,
preferentially, as the phosphate source. Adenosine kinase has broad tissue and
species
distribution, and has been isolated from yeast, a variety of mammalian sources
and certain
microorganisms. It has been found to be present in virtually every human
tissue assayed
including kidney, liver, brain, spleen, placenta and pancreas. Adenosine
kinase is a key
enzyme in the control of the cellular concentrations of adenosine.
Adenosine is a purine nucleoside that is an intermediate in the pathways of
purine
nucleotide degradation and salvage. Adenosine also has many important
physiologic
effects, many of which are mediated through the activation of specific
ectocellular receptors,
termed P 1 receptors (Burnstock, in Cell Membrane Receptors for Drugs and
Hormones,
1978, (Bolis and Straub, eds.) Raven, New York, pp. 107-118; Fredholm, et al.,
Pharrnacol. Rev. 1994, 46: 143-156).
In the central nervous system, adenosine inhibits the release of certain
neurotransmitters (Corradetti, et al., Eur. J. Pharmacol.. 1984, 104: 19-26),
stabilizes
membrane potential (Rudolphi, et al., Cerebrovasc. Brain Metab. Rev. 1992, 4:
346-360).,
functions as an endogenous anticonvulsant (Dragunow, Trends Pharmacol. Sci.
1986, 7:
128-130) and may have a role as an endogenous neuroprotective agent (Rudolphi,
et al.,
Trends Pharmacol. Sci., 1992, 13: 439-445). Adenosine may play a role in
several
disorders of the central nervous system such as schizophrenia, anxiety,
depression and
Parkinson's disease. (Williams, M., in Psychopharmacc~logy: The Fourth
Generation of
Progress; Bloom, Kupfer (eds.), Raven Press, New York, 1995, pp 643-655.
Adenosine has also been implicated in modulating transmission in pain pathways
in
the spinal cord (Sawynok, et al., Br. J. Pharmacol., 1986, 88: 923-930), and
in mediating
the analgesic effects of morphine (Sweeney, et al., J. Pharmacol. Exp. Ther.
1987, 243:
657-665). In the immune system, adenosine inhibits certain neutrophil
functions and
exhibits anti-inflammatory effects (Cronstein, J. Appl. Physiol. 1994, 76: 5-
13). An AK
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inhibitor has been reported to decrease paw swelling in a model of adjuvant
arthritis in rats
(Firestein, et.al., Arthritis and Rheumatism, 1993, 36, S48.
Adenosine also exerts a variety of effects on the cardiovascular system,
including
vasodilation, impairment of atrioventricular conduction and endogenous
cardioprotection in
myocardial ischemia and reperfusion (Mullane and Williams, in Adenosine and
Adenosine
Receptors, 1990 (Williams, ed.) Humana Press, New Jersey, pp. 289-334). The
widespread actions of adenosine also include effects on the renal,
respiratory,
gastrointestinal and reproductive systems, as well as on blood cells and
adipocytes.
Adenosine, via its A1 receptor activation on adipocytes, plays a role in
diabetes by inhibiting
lipolysis (Londos, et al., Proc. Natl. Acad. Sci. USA, 1980, 77, 2551.
Endogenous adenosine release appears to have a role as a natural defense
mechanism
in various pathophysiologic conditions, including cerebral and myocardial
ischemia,
seizures, pain, inflammation and sepsis. While adenosine is normally present
at low levels
in the extracellular space, its release is locally enhanced at the sites) of
excessive cellular
activity, trauma or metabolic stress. Once in the extracellular space,
adenosine activates
specific extracellular receptors to elicit a variety of responses which tend
to restore cellular
function towards normal (Bruns, Nucleosides Nucleotides, 1991, 10: 931-943;
Miller and
Hsu, J. Neurotrauma, 1992, 9: S563-S577). Adenosine has a half-life measured
in
seconds in extracellular fluids (Moser, et al., Am. J. Physiol. 1989, 25: C799-
C806), and
its endogenous actions are therefore highly localized.
The inhibition of adenosine kinase can result in augmentation of the local
adenosine
concentrations at foci of tissue injury, further enhancing cytoprotection.
This effect is likely
to be most pronounced at tissue sites where uauma results in increased
adenosine
production, thereby minimizing systemic toxicities.
Pharmacologic compounds directed towards adenosine kinase inhibition provide
potentially effective new therapies for disorders benefited by the site- and
event-specific
potentiation of adenosine. Disorders where such compounds may be useful
include
ischemic conditions such as cerebral ischemia, myocardial ischemia, angina,
coronary artery
bypass graft surgery (CABG), percutaneous transluminal angioplasty (PTCA),
stroke, other
thrombotic and embolic conditions, and neurological disorders such as
epilepsy, anxiety,
schizophrenia, nociperception including pain perception, neuropathic pain,
visceral pain, as
well as inflammation, arthritis, immunosuppression, sepsis, diabetes and
gastrointestinal
disfunctions such as abnormal gastrointestinal motility.
A number of compounds have been reported to inhibit adenosine kinase. The most
potent of these include 5'-amino-5'-deoxyadenosine (Miller, et al., J. Biol.
Chem. 1979,
254: 2339-2345), 5-iodotubercidin {Wotring and Townsend, Cancer Res. 1979, 39:
3018-
-2-
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3023) and 5'-deoxy-5-iodotubercidin (Davies, et al., Biochem. Pharmacol. 1984,
33: 347-
355).
Adenosine kinase is also responsible for the activation of many
pharmacologically
active nucleosides (Miller, et al., J. Biol. Chem. 1979, 254: 2339-2345),
including
tubercidin, formycin, ribavirin, pyrazofurin and 6-(methylmercapto)purine
riboside. These
purine nucleoside analogs represent an important group of antimetabolites
which possess
cytotoxic, anticancer and antiviral properties. They serve as substrates for
adenosine kinase
and are phosphorylated by the enzyme to generate the active form. The loss of
adenosine
kinase activity has been implicated as a mechanism of cellular resistance to
the
pharmacological effects of these nucleoside analogs (e.~~. Bennett, et al.,
Mol. Pharmacol.,
1966, 2: 432-443; Caldwell, et al., Can. J. Biochem., 1967, 45: 735-744;
Suttle, et al.,
Europ. J. Cancer, 1981, 17: 43-51). Decreased cellular levels of adenosine
kinase have
also been associated with resistance to the toxic effects of 2'-deoxyadenosine
(Hershfield
and Kredich, Proc. Natl. Acad. Sci. USA, 1980, 77: 4292-4296). The
accumulation of
deoxyadenosine triphosphate (dATP), derived from the phosphorylation of 2'-
deoxyadenosine, has been suggested as a toxic mechanism in the immune defect
associated
with inheritable adenosine deaminase deficiency (Kredic:h and Hershfleld, in
The Metabolic
Basis of Inherited Diseases, 1989 (Scryver, et al., eds.), McGraw-Hill, New
York, pp.
1045-1075).
B.S. Hurlbert et al. (J. Med. Chem., 11: 711-717 (1968)) disclose various 2,4-
diaminopyrido[2,3-d]pyrimidine compounds having use as antibacterial agents.
R. K.
Robins et al. (J. Amer. Chem. Soc., $Q:3449-3457 (1958)) disclose methods for
preparing
a number of 2,4-dihydroxy-, 2,4-diamino-, 2-amino-4-hydroxy- and 2-mercapto-4-
hydroxypyrido[2,3-d]pyrimidines having antifolic acid activity. R. Sharma et
al., (Indian J.
Chem., ~1B: 719-720 (1992)) disclose 4-amino-5-(4-chlorophenyl)-7-(4-
nitrophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-~methoxyphenyl)-7-(4-
nitrophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity.
A. Gupta et
al., (J. Indian Chem. Soc., ~1_: 635-636 (1994)) disclose 4-amino-5-(4-
fluorophenyl)-7-
(4-fluorophenyl)pyrido[2,3-d]pyrimidine and 4-amino-5-(4-chlorophenyl)-7-(4-
fluorophenyl)pyrido[2,3-d]pyrimidine compounds having antibacterial activity.
L. Prakash
et al., Pharmazie, 48: 221-222 (1993)) disclose 4-amino-5-phenyl-7-(4-
aminophenyl)pyrido[2,3-d]pyrimidine, 4-amino-5-phenyl-7-(4-
bromophenyl)pyrido[2,3-
d]pyrimidine, 4-amino-5-(4-methoxyphenyI)-7-(4-aminophenyl)pyrido[2,3-
d]pyrimidine,
and 4-amino-5-(4-methoxyphenyl)-7-(4-brornophenyl)pyrido[2,3-d]pyrimidine
compounds
having antifungal activity. P. Victory et al., Tetrahedron, ~: 10253-10258
(1995))
discloses the synthesis of 4-amino-5,7-diphenylpyrido[2,3-d]pyrimidine
compounds from
acyclic precursors. Bridges et al.(PCT application WU 95/19774, published July
27, 1995)
-3-
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disclose various bicyclic heteroaromatic compounds as having utility for
inhibiting tyrosine
kinase of epidermal growth factors.
Summay Of The Invention
The present invention provides for 6,7-disubstituted-4-aminopyrido[2,3-
d]pyrimidine compounds having utility as adenosine kinase inhibitors.
In one aspect, the present invention provides novel compounds having the
formula
(I)
to wherein
R~~N,R2 H
R3
3 N ~ ' ~' 6
2~N N J7 R4
(I)
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken
together with the nitrogen atom to which they are attached to form a 5-to-7
membered ring
optionally containing 1-3 additional heteroatoms selected from O, N or S;
R3 and R4 are independently selected from lowerallcyl, loweralkenyl,
loweralkynyl,
15 aryl, arylalkyl, heteroaryl, or a heterocyclic group and the dashed lines
indicate a double
bond is optionally present.
The present invention also contemplates the pharmaceutically acceptable salts
and
amides of the compounds of Formula I, and the use thereof as provided below.
In another aspect, the present invention provides a method for inhibiting
adenosine
20 kinase by administering a compound of Formula (I).
In particular, the method of inhibiting adenosine kinase comprises exposing an
adenosine kinase to an effective inhibiting amount of a compound of Formula I
of the
present invention. Where the adenosine kinase is located in vivo, the compound
is
administered to the organism.
25 In another aspect, the present invention provides a pharmaceutical
composition
comprising a therapeutically effective amount of a compound of Formula I above
in
combination with a pharmaceutically acceptable carrier.
In still another aspect, the present invention provides a method of treating
ischemia,
neurological disorders, nociperception , inflammation, immunosuppression,
gastrointestinal
30 disfunctions, diabetes and sepsis in a man~unal in need of such treatment,
comprising
administering to the mammal a therapeutically effective amount of a compound
of Formula I
of the present invention.
-4-
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In a preferred aspect, the present invention provides a method of treating
cerebral
ischemia, myocardial ischemia, angina, coronary artery bypass graft surgery,
percutaneous
transluminal angioplasty, stroke, thrombotic and embolic conditions, epilepsy,
anxiety,
schizophrenia, pain perception, neuropathic pain, visceral pain, arthritis,
sepsis, diabetes
and abnorn~al gastrointestinal motility in a mammal in need of such treatment,
comprising
administering to the mammal a therapeutically effective amount of a compound
of Formula I
of the present invention.
The present invention also contemplates the pharmaceutically acceptable salts
and
amides of compounds having Formula I, and their use for inhibiting adenosine
kinase, in
pharmaceutical compositions and for administration to a mammal.
In addition, the present invention relates to a compound of formula (II)
RLN~ R2 H
R3
3N \ \ 6
2~
4
1 N N R (II)
wherein
R 1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken
together with the nitrogen atom to which they are attached to form a 5-to-7
membered ring
optionally containing an additional oxygen or nitrogen atom;
R3 and R4 are independently selected from loweralkyl, loweralkenyl,
loweralkynyl,
aryl, arylalkyl, heteroaryl, or a heterocyclic group.
In another aspect, the present invention provides a process for the
preparation of
compounds of formula II
R ~~N. R2 H
R3
3 (~ \
2~N N R4
1 (In.
wherein
R1 and R2 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or
a
heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group;
the method comprising
(a) reacting 4,6-diamino-5-iodopyrimidine with an ethenylboronic acid
derivative having
the formula
-5-
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~H~~2B~ Rs
wherein R3 is loweratkyl, loweralkenyl, lowerallcynyl, aryl, arylalkyl,
heterocyclic or
heteroaryl or substituted versions thereof, in the presence of
tetraldstriphenylphosphinepalladium(0) and an aqueous alkali metal base, and
isolating a
first intermediate compound having the formula
NH2
N ~ \ R3
'I
_N NH2
(b) reacting the first intermediate compound with an aldehyde compound having
the
formula R4-CHO, wherein R4 is aryl, heteroaryl, or a heterocyclic group, under
anhydrous
conditions and with the removal of the water of reaction, and isolating the
compound of
l0 formula II.
In another aspect, the present invention provides a process for the
preparation of
compounds of formula (II)
R~~ N, R2 H
R3
N N R4 (II),
wherein
i5 Ri and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be
taken together with the nitrogen atom to which they are attached to form a 5-
to-7 membered
ring optionally containing an additional oxygen or nitrogen atom, with the
requirement that
not both Ri and R2 may be hydrogen,
R3 is loweralkyl, lowerallcenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or
a
20 heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group;
the method comprising
(a) reacting a compound having the formula (II)
Ri~N, R2 H
R3
25 N N R4 (II),
wherein
-6-
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Rl and R2 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, hcteroaryl, or
a
heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group;
with a compound selected from the group consisting of
(i) an alkylating agent Rl-Y, wherein R1 is loweralkyl and Y is selected from
the
group consisting of a halide, a mesylate and a tosylate;
(ii) an arylalkylating agent R1-loweralkyl-Y, wherein RZ is arylalkyl and Y is
selected from the group consisting of a halide, a mesylate and a tosylate;
(iii) an acyl compound R1-Z, wherein R1 is an aryl group and Z is selected
from the
group consisting of an acid anhydride maiety, a halide or an acyl activating
group; and isolating the desired compound; and
(b) optionally, when it is desired that R2 should not be hydrogen, treating
the compound
from step (a) with a compound selected from the group consisting of
(i) an alkylating agent R2-Y, wherein R2 is lowerallcyl and Y is selected from
the
group consisting of a halide, a mesylate and a tosylate;
(ii) an arylalkylating agent R2-loweralkyl-Y, wherein R2 is arylalkyl and Y is
selected from the group consisting of a halide, a mesylate and a tosylate;
(iii) an acyl compound R2-Z, wherein R2 is an aryl group and Z is selected
from the
group consisting of an acid anhydride moiety, a halide or an acyl activating
group; and isolating the desired product.
In another aspect, the present invention provides a process for the
preparation of
compounds of formula II
RvN.. R2 H
R3
~N~N~ R4 (n)~
wherein
R1 and R2 are independently H, loweralkyl, arylalkyl or acyl, or may be taken
together with the nitrogen atom to which they are attached to form a 5-to-7
membered ring
optionally containing an additional oxygen or nitrogen atom, with the proviso
that not both
R4 and R5 are hydrogen;
R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl, heteroaryl, or
a
heterocyclic group;
R4 is aryl, heteroaryl, or a heterocyclic group;
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the method comprising
(a) reacting 6-amino-4-chloro-5-iodopyrimidine with an ethenylboronic acid
derivative
having the formula
(HO)2B~Ra
wherein R3 is loweralkyl, loweralkenyl, loweralkynyl, aryl, arylalkyl,
heterocyclic or
heteroaryl, in the presence of tetrakistriphenylphosphinepalladium(0) and an
aqueous alkali
metal base, and isolating a first intermediate compound having the formula
CI
N \ \ R3
I
~N~ NH2
(b) reacting the first intermediate compound with an aldehyde compound having
the
formula R4-CHO, wherein R4 is aryl, heteroaryl, or a heterocyclic group, under
anhydrous
conditions and with the removal of the water of reaction, and isolating the
second
intermediate compound having the formula
CI
R3
N \
II
~N~ N~ R4; and
(c) treating the fourth intermediate compound with an amine compound having
the formula
R1-NH-R2, wherein Rl and R2 are as described above, and isolating the desired
product.
Detailed Description of the Invention
The present invention relates to 6,7-disubstituted-4-aminopyrido[2,3-
d]pyrimidine
compounds that are useful in inhibiting adenosine kinase, to pharmaceutical
compositions
containing such compounds, to a method of using such compounds for inhibiting
adenosine
kinase, and to novel 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine
compounds.
In one aspect, the present invention provides 6,7-disubstituted-4-
aminopyrido[2,3-
d]pyrimidine compounds that are adenosine kinase inhibitors. An adenosine
kinase
inhibitor of the present invention is a compound of the Formula I or II, shown
above.
In a preferred embodiment, an adenosine kinase inhibitor of the present
invention is
a compound of Formula (I) or (II) above, wherein R4 is aryl or heteroaryl and
substituted
versions thereof.
In a more preferred embodiment, an adenosine kinase inhibitor of the present
invention is a compound of Formula (I) or (II) above, wherein R4 is aryl or
heteroaryl or
_g_
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substituted versions thereof and R3 is loweralkyl, aryl, arylalkyl or
heteroaryl or substituted
versions thereof.
In an additional embodiment, the present invention relates to compounds of
formula
I and II as shown above wherein
Rl and R2 are independently selected from H, loweralkyl, arylCl-C6alkyl,
-C(O)Cl-C6alkyl, -C(O)aryl, -C(O)heterocyclic or may join together with the
nitrogen to
which they are attached to from a 5-7 membered ring optionally containing 1-2
additional
heteroatoms selected from O, N or S;
R3 and R4 are independently selected from the group consisting of:
C 1-C6~Yh
C2-C6alkenyl,
C2-C6~YnYl.
C3-Cgcycloalkyl,
heteroarylCp-C6alkyl or substituted heteroarylC~-C6alkyl,
arylCp-C6alkyl or substituted arylCp-C(alkyl,
heteroarylC2-C(alkenyl or substituted heteroarylC2-C(alkenyl,
arylC2-C6aikenyl or substituted arylC2-C6alkenyl,
heteroarylC2-C(alkynyl or substituted heteroarylC2-C6alkynyl,
arylC2-C6alkynyl or substituted arylC2-C6alkynyl wherein the 1-4 heteroaryl or
aryl substituents are independently selected from
halogen, oxo, cyanoCl-C6alkyl, heteroarylCp-C6alkyl, heterocyclicCp-
C6alkyl, C1-Cbalkyloxy, Cl-C6alkyloxyCl-C(alkyl, arylCp-C6alkyl,
arylC1-C6alkyloxy, RSR6NC(O), cyano, CZ-C6alkenyl, C2-C6alkynyl,
C1-C(alkyl, C2-C6alkenyldialkylmalonyl, CF3, HO-, Cl-C(alkyloxyCl-
C(alkyloxy, C1-C6a1ky1SOn wherein n is 1-2, Cl-C6alkylthio, C1-
C6alkylacryl, CF30, CF3, Cl-C4alkylenedioxy, Cl-C6alkylacryl,
RSR6N(CO)NRS, N-formyl(heterocyclic), N02, NRSR6Cp-C(alkyl,
wherein RS and R6 are independently selected from H, Cl-C6alkyl,
HC(O), Cl-C(allcyloxyCl-C6alkyl, C1-C6allcyloxy, C1-
C(~aikylC(O), CF3C(O), NR~RgCI-Cbalkyl, phthalimidoCl-
C6C(O), C1-C(alkylSOn where n is 1-2, CNCI-C(alkyl,
R~RgNC(O)NR~-, heteroaryl, NR~RgCI-C(alkylC(O), Cl-
C(alkyloxycarbamidoCl-C6allcyl,
wherein R~ and Rg are independently selected from those
variables identified for R~ and R6 or
_9_
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RS and R6 or R~ and R8 may join together with the nitrogen atom to
which they are attached to form a 5-7 membered unsubstituted or
substituted ring optionally containing 1-3 additional heteroatoms
selected from O, IV or S wherein the substituents are selected from
Cl-CSalkyl and wherein, in the case of formula I,
a dashed line --- indicates a double bond is optionally present. The present
invention also
includes those compounds having R3 and R4 independently selected from those
groups
shown below as 6-substituted groups and as 7-substituted groups.
Exemplary and preferred compounds of the invention include:
4-amino-6-phenyl-7-(p-dimethylaminophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pY~dine;
4-amino-6-(4-methylphenyl)-7-phenylpyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(4-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(5-pyrimidinyl)phenyl)pyrido[2,3-
d]pyrimidine;;
4-amino-6-(4-methylphenyl)-7-(4-(2-(2-pyridinyl)ethenyl)phenyl)pyrido(2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(thiophen-3-yl)pyrido[2,3-d]pyrimidine;
4-amino-b-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(2-pyridinyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl}-7-(3,4-methylenedioxyphenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-butyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-butyl-7-(thiophen-3-yl)pyrido [2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-bromothiophen-2-yl)pyrido [2,3-d]pyrimidine;
4-amino-6-(4-methyiphenyl}-7-(5-methylthiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethoxy)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-phenoxyphenyl}pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-d] pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-bromothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-methylthiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(furan-2-yl)pyrido[2,3-d]pyrimidine;
-10-
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4-amino-6-(4-methylphenyl)-7-(furan-3-yl)pyrido[2,3-d)pyrimidine;
4-amino-6-(4-methylphenyl)-7-(5-methyl-furan-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-{2-propyl)phenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(S-nitrothiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-(dimethylamino)phenyl)-7-(thiophen-2-yl}pyrido[2,3-d]pyrimidine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(thiophen-2-yl)pyrido[2,3-d)pyrinudine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(5-nitrothiophen-2-yl)pyrido[2,3-
d]pyrimidine;
4-amino-6-hexyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d)pyrimidine;
l0 4-amino-6-hexyl-7-(thiophen-2-yi)pyrido[2,3-d)pyrimidine;
4-amino-6-(2-methyl-2-propyl)-7-(thiophen-2-yl)pyrido[2,3-d)pyrimidine;
4-amino-6-(4-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d)pyrimidine;
4-amino-6-(4-propylphenyl}-7-(4-(dimethylamino)phenyl)pyrido[2,3-d)pyrimidine;
4-amino-6-(3,4-dimethoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(3-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(3-bromophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d)pyrimidine;
4-amino-6-(3-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d)pyrimidine;
4-amino-6-(3-trifluoromethylphenyI}-7-(4-(dimethylamino)phenyl}pyrido[2,3-
d]pyrimidine;
4-amino-6-(3-chlorophenyl)-7-(4-(dimethylamino}phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3,5-dichlorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(3,4-methylenedioxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d)pyrimidine;
4-amino-6-(3,4-methylenedioxyphenyl}-7-(thiophen-2-yl)pyrido[2,3-d)pyrimidine;
4-amino-6-(3-methoxycarbonylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d)pyrimidine;
4-amino-6-(3-(2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d)pyrimidine;
4-amino-6-(4-(2-methyl-2-propyl)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-fluorophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methoxyphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
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4-amino-6-(3-(phenylmethoxy)phenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3
d]pyrimidine;
4-amino-6-(4-chlorophenyl)-7-(4-(dimethylamino~henyl)pyrido[2,3-d]pyrimidine;
4-amino-6-{3-fluoro-4-methylphenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(3-fluoro-4-methylphenyl}-7-(thiophen-2-yl)pyrido [2,3-d]pyrimidine;
4-amino-6-(3-phenylpropyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3-phenylpropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(2-phenylethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(phenylmethyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(cyclohexylmethyl}-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-butyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-pentyl-7-(4-(dimethylamino)phenyl)pyrido[2,3-d)pyrimidine;
4-amino-6-(2-methylpropyl)-7-(4-{dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-propyl-7-(4-{dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3-cyanopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3-nitrophenyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-pentyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(3-carboxamidopropyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-((4-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-({3-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((4-(2-propyl)phenyl)methyl)-7-{thiophen-2-yl)pyrido[2,3-
d]pyrimidine;
4-amino-6-((4-methoxyphenyl)methyl)-7-(4-(2-propyl)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-((4-bromophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((3-fluorophenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((4-bromophenyl)methyl)-7-(thiazole-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((3-methoxyphenyl)methyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(phenylmethyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-((3-methoxyphenyl)methyl)-7-(4-(dimethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(trifluoromethyl)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-methylphenyl}pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-ethylphenyl)pyrido[2,3-d]pyrimidine;
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4-amino-b-(4-mcthylphenyl)-7-(4-cyanophenyl}pyrido[2,3-d]pyrimidine;
4-amino-b-(4-methylphenyl)-7-(4-acetamidophenyl)pyrido [2,3-d]pyrimidine;
4-amino-b-(4-methylphenyl)-7-(4-phenoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-nitrophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-fluorophenyl;Ipyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-chlorophenyl)pyrido[2,3-d]pyrimidine;
4-amino-b-(4-methylphenyl)-7-(4-aminophenyl;lpyrido(2,3-d]pyrimidine;
4-amino-b-(4-methylphenyl)-7-(4-methylthiophenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-((4-phenyl)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-((4-phenylmethoxy)phenyl)pyrido[2,3-d]pyrimidine;
4-amino-b-(4-methylphenyl)-7-((4-N,N-diethylamino)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-((4-2-phenylethenyl)phenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-(2-methyl-2-propoxy)phenyl)pyrido(2,3-
dJpyrimidine;
4-amino-6-(4-methylphenyl)-7-(3-chlorophenyl}pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(3,5-dimethoxyphenyl)pyrido[2,3-d)pyrimidine;
4-amino-6-(thiophen-2-yl)-7-(4-N,N-dimethylaminophenyl)pyrido[2,3-
d]pyrimidine;
4-amino-6-(4-methylphenyl}-7-(benzofuran-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(thiophen-2-yl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(thiophen-2-yl)-7-(4-methoxyphenyl;Ipyrido[2,3-d]pyrimidine;
4-amino-6-(4-bromophenyl)-7-(4-N,N-dimethylaminophenyl)pyrido[2,3-
d]pylvnidine;
4-amino-6-(3-bromo-4-methoxyphenyl)-7-(4-N,N-dimethylaminophenyl)-
pyrido[2,3-d]pyrimidine;
4-amino-6-(3-bromo-4-methoxyphenyi)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methylphenyl)-7-(4-butoxyphenyl)pyrido[2,3-d]pyrimidine;
4-amino-6-(4-methjrlphenyl)-7-(3-methoxyphenyl)pyrido[2,3-d]pyrimidine; and
4-amino-6-(4-methylphenyl)-7-(3,5-dichlorophenyl)pyrido[2,3-d]pyrimidine.
The present invention also includes those reduced versions of the compounds
described above wherein the right side of the bicyclic ring may be reduced or
partially
reduced as shown in formula I via catalytic hydrogenation or other known
reduction process
to form compounds as above wherein the 5,6 and/or the 7,8 double bond is
absent or where
there is a double bond between the 6 and 7 carbons. It is contemplated that
the final
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compounds shown above may be readily reduced and thus these compounds are
within the
scope of the invention.
In addition, R3 and R4 may independently be selected fromphenyl; thiophen-2-
yl; 1-
methyl-2-oxobenzoxazolin-5-yl; 2-(dimethylamino)-5-pyrimidinyl; 2-(N-formyl-N-
methyl
amino)-3-pyrimidinyl; 2-(N-(2-methoxyethyl)-N-methyl amino)-5-pyrimidinyl; 2-
(N-
methylamino)5-pyrimidinyl; 2-{1-morpholinyl)-5-pyrimidinyl; 2-(1-
pyrrolidinyl~5-
pyrimidinyl; 2-dimethylamino-S-pyrimidinyl; 2-furanyl; 2-oxobenzoxazolin-5-yl;
2-pyridyl;
3-(dimethylamino)phenyl; 3-amino-4-methoxyphenyl; 3-bromo-4-
(dimethylamino)phenyl;
3-methoxyphenyl; 3-methyl-4-{N-acetyl-N-methylamino)phenyl; 3-methyl-4-(N-
formyl-N~-
methylamino)phenyl; 3-methyl-4-(N-methyl-N-(trifluoroacetyl)amino)phenyl; 3-
methyl-4-
(N-methylamino)phenyl; 3-methyl-4-pyrrolidinylphenyl; 3-pyridyl; 3,4-
dichlorophenyl;
3,4-methylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 4-(acetylamino)phenyl; 4-
(dimethylamino)-3-fluorophenyl; 4-(dimethylamino)phenyl; 4-(imidazol-1-
yl)phenyl; 4-
(methylthio)phenyl; 4-(morpholinyl)phenyl; 4-(N-(2-
(dimethylamino)ethyl)amino)phenyl;
4-(N-(2-methoxyethyl)amino)phenyl; 4-(N-acetyl-N-methylamino)phenyl; 4-(N-
ethyl-N-
formylamino)phenyl; 4-(N-ethylamino)phenyl; 4-(N-formyl-N-{2-
methoxyethyl)amino)phenyl; 4-(N-isopropylamino)phenyl; 4-(N-methyl-N-((2-
dimethylamino)ethyl)amino)phenyl; 4-(N-methyl-N-(2-(N-
phthalimidyl)acetyl)amino)phenyl; 4-(N-methyl-N-(2-cyano)ethylamino)phenyi; 4-
(N-
methyl-N-(2-methoxyethyl)amino)phenyl; 4-(N-methyl-N-(3-
methoxy)propionylamino)phenyl; 4-(N-methyl-N-acetylamino)phenyl; 4-(N-methyl-N-
formylamino)phenyl; 4-(N-methyl-N-trifluoroacetylamino)phenyi; 4-(N-
morpholinyl)phenyl; 4-(thivphen-2-yl)phenyl; 4-(ureido)phenyl; 4-(2-
(dimethylamino)acetylamino)phenyl; 4-(2-(2-
methoxy)acetylamino)ethyl)amino)phenyl; 4-
(2-methoxy)ethoxyphenyl; 4-(2-oxo-1-oxazolidinyl)phenyl; 4-{4-methoxy-2-
butyl)phenyl;
4-(4-methylpiperidinyl)phenyl; 4-(5-pyrimidinyl)phenyl; 4-aminophenyl; 4-
bromophenyl;
4-butoxyphenyl; 4-carboxamidophenyl; 4-chlorophenyl; 4-cyanophenyl; 4-
diethylaminophenyl; 4-diethylmalonylallylphenyl); 4-dimethylaminophenyl; 4-
ethoxyphenyl; 4-ethylphenyl; 4-fluorophenyl; 4-hydroxyphenyl; 4-
imidazolylphenyl; 4-
iodophenyl; 4-isopropylphenyl; 4-methoxyphenyl) 4-methylaminophenyl; 4-
methylsulfonylphenyl; 4-morpholinylphenyl; 4-N-(2-(dimethylamino)ethyl)-N-
formylamino)phenyl; 4-N-(3-methvxypropionyl)-N-isopropyl-amino)phenyl; 4-N-
ethyl-N-
(2-methoxyethyl)amino)phenyl; 4-N-formylpiperidinylphenyl; 4-nitrophenyl; 4-
piperidinylphenyl; 4-pyridylphenyl; 4-pyrrolidinylphenyl; 4-t-
butylacrylphcnyl; 5-
(dimethylamino)thiophen-2-yl; 5-amino-2-pyridyl; 5-dimethylamino-2-pyrazinyl;
3-
dimethylaminopyridazin-6-yl; 5-dimethylamino-2-pyridyl; 5-pyrimidinylphenyl; 6-
(N-
methyl-N-formylamino)-3-pyridinyl; 6-(N-methyl-N-(2-methoxyethyl)amino)-3-
pyridinyl;
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6-(2-oxo-oxazolidinyl)-3-pylzdinyl; 6-dimethylamino-3-pyridinyl; 6-imidazolyl-
3-pyridinyl;
6-morpholinyl-3-pyridinyl; 6-pyrrolidinyt-3-pyridinyl; (2-propyl)-3-pyridinyl;
and (4-
formylamino)phenyl; (thiophen-2-yl)methyl; (thiophen-3-yl)methyl; butyl;
cycloheptyl;
pentyl; thiophen-2-yl; I-(3-bromophenyl)ethyl; 2-(N-
phenylmethoxycarbonyl)aminophenyl;
2-(3-bromophenyl)ethyl; 2-(3-cyanophenyl)methyl; 2-(4-bromophenyl)eihyl; 2-(5-
chloro-2-
(thiophen-3-yl)phenyl; 2-bromophenyl; 2-furanyl; 2-methylpropyl; 2-
phenylethyl;
phenylmethyl; 2,3-dimethoxyphenyl; 2,3-methylenedioxyphenyl; 3-(furan-2-
yl)phenyl; 3-
(thiophen-2-yl)phenyl; 3-(2-pyridyl)phenyl; 3-(3-methoxybenzyl)phenyl; 3-
(amino)propyn~rl; 3-benzyloxyphenyl; 3-bromo-4-fluorophenyl; 3-bromo-5-
iodophenyl; 3-
bromo-5-methoxyphenyl; 3-bromophenyl; 3-bromophenylmethyl; 3-
carboxamidophenyl; 3-
chlorophenyl; 3-cyanophenyl; 3-diethylmalonylallylphenyl; 3-
dimethylaminophenyl; 3-
ethoxyphenyl; 3-fluoro-5-trifluoromethylphenyl; 3-fluorophenyl; 3-
hydroxyphenyl; 3-
iodophenyl; 3-methoxyethyoxyphenyl; 3-methoxyphenyl; 3-methylphenyl; 3-
meihylsulfonylphenyl; 3-mcthylthiophenyl; 3-t-butylacrylphenyl; 3-
trifloromethyoxyphenyl;
3-trifluoromethylphenyl; 3-vinylpyridinylphenyt; 3,4-dichlorophenyl; 3,4-
dimethoxyphenyl;
3,4-rnethylenedioxyphenyl; 3,4,5-trimethoxyphenyl; 3,5-
di(irifluoromethyl)phenyl; 3,5-
dibromophenyl; 3,5-dichlorophenyl; 3,5-dimethoxyphenyl; 3,5-dimethylphenyl; 4-
(2-
propyl)phenyl; 4-(2-propyl)oxyphenyl; 4-benzyloxyphenyl; 4-bromophenyl; 4-
bromothiophen-2-yl; 4-butoxyphenyl; 4-dimethylaminophenyl; 4-fluoro-3-
trifluoromethylphenyl; 4-methoxyphenyl; 4-neopentylphenyl; 4-phenoxyphenyl; 5-
bromothiophen-2-yl; 5-cyclohexyl; 5-cyclopropyl; S-hexyl; 5-methyl; 5-phenyl;
(2-bromo-
5-chlorophenyl)methyl; (2-bromophenyl)methyl; and (S-chloro-2-(3-
methoxyphenyl)phenyl)methyl or other groups as specified herein.
The term "acyl", as used herein, refers to a moiety attached by a carbonyl
linkage, as
for example, loweralkyl-carbonyl or aryl-carbonyl, wherein loweralkyl and aryl
are as
defined herein. Examples of acyi include, for example, acetyl, propionyl,
hexanoyl,
trifluoroacetyl, benzoyl, 4-methylbenzoyl, methoxyacetyl, pentanoyl, N-
Bocglycyiimidazoyl, N-phthalimidylglycyl and the like or others as specified
herein.
The term "aryl" or "substituted aryl", as used herein, refers to a carbocyclic
aromatic
radical, including, for example, phenyl and I- or 2-naphthyl, which may be
unsubstituted
or substituted by independent replacement of one, two or three of the hydrogen
atoms
thereon with Cl, Br, F, I, cyano, carboxamido, hydroxy, loweralkoxy,
loweralkyl,
loweralkenyl, ioweralkynyl, amino, loweralkylamino, di(loweralkylamino), N-
loweralkyl-
N-loweralkoxyamino, irifluoromethyl or methoxymethyl groups. In addition, the
term
"aryl" refers to a phenyl group substituted with one ureido, methylsulfonyl,
pyrimidinyl,
pyridinyl, pyridazinyl, morpholinyl, phenyl-lowerlalkoxy, phenyl-loweralkenyl
or
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cycloallcyl-loweralkyl group. Examples of aryl radicals include, but are not
limited to, 3-
bromophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, 3-(2-
propyl)phenyl,
3,4-dimethoxyphenyl, 3-trifluoromethylphenyl, 3-trifluoro-4-fluorophenyl, 4-(N-
methyl-
N-methoxyl)ethylaminophenyl, 4-dimethylaminophenyl, 3-fluoro-4-methylphenyl, 4-
methylphenyl, 4-cyanophenyl, 4-propylmethyl, 3,5-dichlorophenyl, 3,4-
methylenedioxyphenyl, 3-cyanopropylphenyl, 4-ureidophenyl, 3-
methylsulfonylphenyl, 3-
carboxamidopropylphenyl or others as shown herein.
The term "arylalkyl" refers to a loweralkyl radical having appended thereto an
aryl
group, as defined above, as for example benzyl and phenylethyl.
The term "aryloxy" refers to a aryl radical which is appended to the molecule
via an
ether linkage (i.e., through an oxygen atom), as for example phenoxy,
naphthyloxy, 4-
chlorophenoxy, 4-methylphenoxy, 3,5-dimethoxyphenoxy, and the like.
The term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having
from 3
to 7 ring atoms. Exari~ples of cycloallcyl include cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl and cycloheptyl. Cycloalkyl is also described as C3-Cgcycloallcyl.
The term "cycloalkyl-lowerallcyl" refers to a loweralkyl radical as defined
below
substituted with a cycloalkyl group as defined above by replacement of one
hydrogen atom.
Examples of cycloalkyl-loweralkyi include cyclopropylmethyl, cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl and cycloheptylbutyl, and the like.
The term "heteroaryl" refers to a monocyclic aromatic radical having from five
to
seven ring atoms of which one ring atom is nitrogen, oxygen or sulfur; zero,
one or two
ring atoms are additional heteroatoms independently selected from S, O and N;
and the
remaining ring atoms are carbon, the radical being joined to the rest of the
molecule via any
of the ring atoms. A heteroaryl group may be unsubstituted or substituted by
independent
replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F,
I, cyano,
carboxamido, hydroxy, loweraikoxy, loweralkyl, loweralkenyl, loweralkynyl,
amino,
loweralkylamino, di(loweralkylamino), N-loweralkyl-N-lowerallcoxyamino,
trifluoromethyl
or methoxymethyl groups. In addition, the term "heteroaryl " refers to a
heteroaryl group
substituted with one ureido, methylsulfonyl, pyrimidinyl, pyridinyl,
pyridazinyl,
morpholinyl, phenyl-lowerlalkoxy, phenyl-loweralkenyl or cycloallcyl-
loweralkyl group.
In addition a heteroaryl group may be substituted by replacement of any two
adjacent
hydrogen atoms with a grouping of atoms to form a fused benzene ring. Examples
of
heteroaryl include pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl,
thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, furanyl,
thiophenyl, 5-
methylthiophen-2-yl, 5-nitrothiophen-2-yl, 5-methylfuranyl, benzofuranyl,
benzothiophenyl, and the like and others as shown herein.
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The term "heterocycfic" refers to a saturated or unsaturated monocyclic ring
system
radical having from four to seven ring atoms of which one is nitrogen or
oxygen; one or two
ring atoms are additional heteroatoms independently selected from S, O and N;
and the
remainder are carbon, the radical being joined to the rest of the molecule via
any of the ring
atoms and being optionally substituted, either on a nitrogen or a carbon atom,
by an
additional radical selected from among aryl(loweralkyl), alkoxycarbonyl,
loweralkyl,
halo(loweralkyl), amino(loweralkyl), hydroxy-substituted loweralkyl, hydroxy,
lowerallcoxy, halogen, amino, loweraikylamino, and amino, (lowerallcyl)amino
or
alkanoylamino of from one to eight carbon atoms in which the amino group may
be further
l0 substituted with alkanoyl of from one to eight carbons, an alpha-amino acid
or a
polypeptide. Examples of heterocyclic include pyrrolidine, tetrahydrofuran,
dihydropyrrole, isoxazolidine, oxazolidine, tetrahydropyridine, piperidine,
piperazine,
morpholine, thiomorpholine, aziridine and azetidine and those additionally
described herein.
The term "heterocyclic-loweralkyl" refers to a lowerallryl radical as defined
below
substituted with a heterocyclic-group as defined above by replacement of one
hydrogen
atom. Examples of cycloallcyl-loweralkyl include pyrrolidinylmethyl,
piperidinylethyl, and
the like.
The term "lowerallcyl", as used herein, refers to saturated, straight- or
branched-
chain hydrocarbon radicals containing from one to six carbon atoms including,
which may
be unsubstituted or substituted by independent replacement of one, two or
three of the
hydrogen atoms thereon with CI, Br, F, I, cyano, carboxamido, hydroxy,
loweralkoxy,
amino, loweralkylamino, di(loweralkylamino) or N-lowc:ralkyl-N-
loweralkoxyamino
groups. Examples of loweralkyl include, but are not limited to, methyl, ethyl,
propyl,
isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, hydroxyethyl,
methoxymethyl,
trifluoromethyl, 3-cyanopropyl, 3-carboxamidopropyl, and the like. In certain
cases, the
group "C1-C6alkyl" is described and has a similar meaning as above for
loweralkyl but is
more specifically recited. Likewise, the term "Cp-C6alkyl" indicates the
carbon atoms
which may be present in the alkyl chain including zero. 'These terms are also
provided
adjacent to aryl or heteroaryl or other generic group and represent or have
the same meaning
as, for example, "arylalkyl'.' or "heteroarylalkyl".
The term "lowerallcenyl", as used herein, refers to mono-unsaturated straight-
or
branched-chain hydrocarbon radicals containing from two to six carbon atoms
including,
but not limited to, vinyl, propenyl, n-butenyl, i-butenyl, n-pentenyl, and n-
hexenyl. These
variables are also recited as, for example, C2-C6alkenyl.
The term "loweralkoxy" refers to a loweralkyl radical which is appended to the
molecule via an ether linkage (i.e., through an oxygen atom), as for example
methoxy,
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ethoxy, propoxy, 2-propoxy, 2-methyl-2-propoxy, tert-butoxy, pentyloxy,
hexyloxy,
isomeric foams thereof and the Like. This term is also described as Cl-
C6alkyloxy.
The term "loweralkynyl", as used herein, refers to straight- or branched-chain
hydrocarbon radicals possessing a single triple bond and containing from two
to six carbon
atoms including, but not limited to, ethynyl, propynyl, n-butynyl, n-pentynyl,
and n-
hexynyl. This term is also described as C2-C6alkynyl.
The term "mammal" has its ordinary meaning and includes human beings.
In a further aspect of the present invention pharmaceutical compositions are
disclosed which comprise a compound of the present invention in combination
with a
pharmaceutically acceptable carrier.
The present invention includes one or more compounds, as set forth above,
formulated into compositions together with one or more non-toxic
physiologically tolerable
or acceptable diluents, carriers, adjuvants or vehicles that are collectively
referred to herein
as diluents, for parenteral injection, for oral administration in solid or
liquid form, for rectal
i5 or topical administration, or the Like. As is well known in the art, a
compound of the
present invention can exist in a variety of forms including pharmaceutically-
acceptable salts,
amides and the Like.
Compositions may be prepared that will deliver the correct amount of a
compound
or compounds of the invention. The following dosages are thought to provide
the optimal
2o therapy: iv infusions: 0.1- 250 nmol/kg/minute, preferably from I-50
nmol/kg/minute;
oral: 0.01-250 ~.Mol/kg/day, preferably from about 0.1-50 ~,Mol/kg/day; these
oral molar
dosage ranges correspond to 0.005-125 mg/kg/day, preferably 0.05-25 mg/kg/day.
For
treatment of acute disorders the preferred route of administration is
intravenous; the
preferred method of treating chronic disorders is orally by means of a tablet
or sustained
25 release formulation.
"Pharmaceutically-acceptable amide" refers to the pharmaceutically-acceptable,
nontoxic amides of the compounds of the present invention which include amides
formed
with suitable organic acids or with amino acids, including short peptides
consisting of from
1-to-6 amino acids joined by amide linkages which may be branched or linear,
wherein the
30 amino acids are selected independently from naturally-occurring amino
acids, such as for
example, glycine, alanine, leucine, valine, phenylalanine, proline,
methionine, tryptophan,
asparagine, aspartic acid, glutamic acid, glutamine, serine, threonine,
lysine, arginine,
tyrosine, histidine, ornithine, and the like.
"Pharmaceutically-acceptable salts" refers to the pharmaceutically-acceptable,
35 nontoxic, inorganic or organic acid addition salts of the compounds of the
present
invention, as described in greater detail below.
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The term "substituted versions thereof' refers to those generic groups such as
aryl
or heteroaryl or heterocyclic which have substituents around the aryl,
heteroaryl,
heterocyclic or other genera variable at chemically appropriate positions and
as designated or
exemplified herein.
The compounds of the present invention can be used in the form of
pharmaceutically-acceptable salts derived from inorganic or organic acids.
These salts
include, but are not limited to, the following: acetate, adipate, alginate,
aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionatc, digluconate, dodecylsulfate, ethanesulfonate,
flavianate, fumarate,
glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexonoate,
hydrochloride,
hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,
methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,
pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivaiate, propionate,
succinate, tartrate,
' thiocyanate, tosylate, and undecanoate.
Appropriate cationic salts are also readily prepared by conventional
procedures such
as treating an acid of Formula I with an appropriate amount of base, such as
an alkali or
alkaline earth metal hydroxide, e.g., sodium, potassium, lithium, calcium, or
magnesium,
or an organic base such as an amine, e.g., dibenzylethylenediamine,
cyclohexylamine,
dicyclohexylamine, triethylamine, piperidine, pyrrolidine, benzylamine, and
the like, or a
quanternary ammonium hydroxide such as tetramethylammonium hydroxide and the
like.
Also, the basic nitrogen-containing groups can be quaternized with such agents
as
loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,
bromides, and
iodides; dialkyl sulfates; long chain halides such as decyl, lauryl, myristyl,
and stearyl
chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl
bromides, and
others. Water or oil-soluble or dispersible products are thereby obtained.
The salts of the present invention can be synthesized from the compounds of
Formula I or II which contain a basic or acidic moiety by conventional
methods, such as by
reacting the free base or acid with stoichiometric amounts or with an excess
of the desired
salt forming inorganic acid or base in a suitable solvent or various
combinations of solvents.
Further included within the scope of the present invention are pharmaceutical
compositions comprising one or more of the compounds of formula (I} prepared
and
formulated in combination with one or more non-toxic pharmaceutically
acceptable carriers
compositions, in the manner described below.
Compositions suitable for parenteral injection may comprise pharmaceutically
acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions
or emulsions
and sterile powders for reconstitution into sterile injectable solutions or
dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or
vehicles
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include water, ethanol, polyols (propylene glycol, polyethylene glycol,
glycerol, and the
like), suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic
esters such as ethyl oleate. Proper fluidity may be maintained, for example,
by the use of a
coating such as lecithin, by the maintenance of the required particle size in
the case of
dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting,
emulsifying, and dispersing agents. Prevention of the action of microorganisms
may be
ensured by various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to
include isotonic
agents, for example, sugars, sodium chloride and the like. Prolonged
absorption of the
injectable pharmaceutical form may be brought about by the use of agents
delaying
absorption, for example, aluminum monostearate and gelatin.
If desired, and for more effective distribution, the compounds may be
incorporated
into slow-release or targeted-delivery systems, such as polymer matrices,
liposomes, and
microspheres. They may be sterilized, for example, by filtration through a
bacteria-
retaining filter, or by incorporating sterilizing agents in the form of
sterile solid
compositions, which may be dissolved in sterile water, or some other sterile
injectable
medium immediately before use.
Solid dosage forms for oral administration may include capsules, tablets,
pills,
powders, and granules. In such solid dosage forms, the active compound is
admixed with
at least one inert customary excipient (or carrier), such as sodium citrate or
dicalcium
phosphate, and additionally {a) fillers or extenders, as for example,
starches, lactose,
sucrose, glucose, mannitol and silicic acid; (b) binders, as for example,
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and
acacia; (c)
humectants, as for example, glycerol; (d) disintegrating agents, as for
example, agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain complex
silicates and
sodium carbonate; {e) solution retarders, as for example paraffin; (f)
absorption
accelerators, as for example, quaternary ammonium compounds; (g) wetting
agents, as for
example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for
example, kaolin
and bentonite; and (i) lubricants, as for example, talc, calcium stearate,
magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the
case of
capsules, tablets and pills, the dosage forms may also comprise buffering
agents.
Solid compositions of a similar type may also be employed as fillers in soft
and
hard-filled gelatin capsules, using such excipients as lactose or milk sugar,
as well as high
molecular weight polyethylene glycols, and the like. '
Solid dosage forms such as tablets, dragees, capsules, pills and granules may
be
prepared with coatings and shells, such as enteric coatings and others well
known in this
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art. They may contain pacifying agents, and may also be of such composition
that they
release the active compound or compounds in a certain part of the intestinal
tract in a delayed
manner. Examples of embedding compositions which may be used are polymeric
substances and waxes.
The active compounds may also be in micro-encapsulated form, if appropriate,
with
one or more of the above-mentioned excipients.
Liquid dosage fomls for oral administration include pharmaceutically
acceptable
emulsions, solutions, suspensions, syrups and elixirs. In addition to the
active
compounds, the liquid dosage forms may contain inert diluents commonly used in
the art,
such as water or other solvents, solubilizing agents and emulsifiers, as for
example, ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular,
cottonseed
oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil,
glycerol,
tetrahydmfurfuryl alcohol, polyethylene glycols and fatty acid esters of
sorbitan or mixtures
of these substances, and the like.
Besides such inert diluents, these liquid dosage forms may also include
adjuvants,
such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring and
perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending
agents,
as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-
agar and
tragacanth, or mixtures of these substances, and the like.
Compositions for rectal or vaginal administrations are preferably
suppositories
which can be prepared by mixing the compounds of this invention with suitable
non-
irritating excipients or carriers such as cocoa butter, polyethylene glycol or
a suppository
wax, which are solid at ordinary temperatures but liquid at body temperature
and therefore,
melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical or transdermal administration of a compound of this
invention further include ointments, pastes, creams, lotions, gels, powders,
solutions,
sprays, inhalants or transdermal patches. Transdermal administration via a
transdermal
patch is a particularly effective and preferred dosage form of the present
invention. The
active component is admixed under sterile conditions with a pharmaceutically
acceptable
carrier and any needed preservative, buffers or propellants as may be
required. It is known
that some agents may require special handling in the preparation of
transdermal paitch
formulations. For example, compounds that are volatile in nature may require
admixture
with special formulating agents or with special packaging materials to assure
proper dosage
delivery. In addition, compounds which are very rapidly absorbed through the
skin may
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require formulation with absorption-retarding agents or barriers. Ophthalmic
formulations,
eye ointments, powders and solutions are also contemplated as being within the
scope of
this invention.
The present compounds may also be administered in the form of liposomes. As is
known in the art, liposomes are generally derived from phospholipids or other
lipid
substances. Liposomes are formed by mono- or mufti-lamellar hydrated liquid
crystals that
are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable
and
metabolizable lipid capable of forming liposomes may be used. The present
compositions
in liposome foml may contain, in addition to the compounds of the present
invention,
stabilizers, preservatives, excipients, and the like. The preferred lipids are
the
phospholipids and the phosphatidyl cholines (lecithins), both natural and
synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott,
Ed., Methods
in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p 33 et
seq.
Synthetic Methods
The compounds and processes of the present invention will be better understood
in
connection with the following synthetic Schemes 1 and 2 which illustrate the
methods by
which the compounds of the invention may be prepared. The groups R1, R2, R3
and R4
are as defined above unless otherwise noted.
Scheme 1
NH2 NH2
N ~ ~ + ~H0~2B~Ra ~ \ R3
N NH2 N NH2
2 3
NH2
N ~ \ R3 H N H2 s
+ O~ R4 ---~ N \ \ R
N N tie N~ N ~ Ra
3 4
5
In aCCOrdance with Scheme 1 are prepared compounds of Formula (II) wherein Rl
and R2 are hydrogen. A starting material, 4,6-diamino-S-iodopyrimidine (1), is
reacted
with ethenylboronic acid derivatives (2), wherein R3 is loweralkyl,
loweralkenyl,
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loweralkynyl, aryl, arylalkyl, hcoerocyclic or heteroaryl or substituted
versions thereof, to
prepare compound (3) in the presence of tetrakistriphenylphosphinepalladium(0)
or other
suitable palladium(0) complexes, and aqueous allcali metal base, such as
sodium or
potassium hydroxide, for example, preferably buffered with an aqueous sodium
or
potassium bicarbonate at reflux for about 8 to about 24 hours. Compound ( 1 )
may be
prepared from 4,6-diaminopyridine by treatment with iodine in DMF at about 40
°C to about
50 °C for about 24 hours in the presence of potassium carbonate.
Compounds of formula
(2) may be prepared by reaction of an R3-substituted acetylene with
catecholborane in a
solvent such as THF. R3-substituted acetylenes may be prepared according to
various
literature procedures, such as, for example, Van Hijfte et al., Tetrahedron
Letters, 1989,
~Q 3655; Tao et al., J. Org.Chem., 1990, ,5~: 63; and Rossi et al., Gazz.
Chim. Ital.,
1990, 1~: 783-791.
Compound (3) is then reacted with the aldehyde compound (4), wherein R4 is
aryl,
heteroaryl, or a heterocyclic group, to prepare compound (5) in a suitable
anhydrous
solvent, under Suzuki reaction conditions, such as Biphenyl ether, 1,2,4-
trichlorobenzene,
toluene, or the like, in the presence of 4A molecular sieves to adsorb the
water of reaction,
at reflux for from about 2 to about 24 hours. Compounds (5) are compounds of
Formula
(II) wherein R1 and R2 are hydrogen. The compounds prepared according to
Scheme 1
may be further treated with a suitable reducing agent such as hydrogen in the
presence of a
catalyst or other reducing agent to form the 5,6 and/or 7,8 reduced versions
of a compound
of formula II. In addition, reduction can proceed to form single bonds at the
5,6 and 7,8
positions and a double bond between the 6, 7 carbons. In the former case(s),
stereoisomers
are formed and are included within the scope of the invention. These isomers
may be
isolated by conventional means.
h 2
Rj R2
N H2 y.
N ~ ~ R3 R$
N ~
N N R4 ~N~ N~ R4
5 6
In accordance with Scheme 2, compounds of Formula (II) wherein one or both of
R1 and R2 are loweralkyl, arylalkyl or acyl, may be prepared by treatment of
compound (5)
with the appropriate reagent. To prepare compounds of formula (I) or (II)
wherein R1 and
R2 are not both hydrogen atoms, it is possible to prepared the desired
derivative from the
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compound of Formula (I) wherein R1 and R2 are both hydrogen atoms. When R1 or
R2 is
loweralkyl this may be accomplished by reaction of the free amino group with
the
appropriate alkylating reagent, such as an alkyl halide, an alkyl mesylate or
an alkyl tosylate,
for example, in the presence of a base such as triethylamine or potassium
carbonate in a
suitable solvent, such as for example, methylene chloride or THF. When R1 or
R2 is
arylalkyl this may be accomplished by reaction of the free amino group with
the appropriate
arylalkyl halide, an alkyl mesylate or an alkyl tosylate, for example, in the
presence of a
base such as triethylamine or potassium carbonate in a suitable solvent, such
as for example,
methylene chloride or THF. When R1 or R2 is acyl this may be accomplished by
reaction of
the free amino group with the appropriate acid anhydride, an acyl halide such
as acyl
chloride, or an activated acyl group, such as an acyl cyanide, an acyl azide
or a thiolester, in
the presence of a base such as triethylamine or potassium carbonate in a
suitable solvent,
such as for example, methylene chloride or THF. When R1 and R2 are taken
together with
the nitrogen atom to which they are attached to form a 5-to-7 membered ring
optionally
containing an additional oxygen or nitrogen atom, the compound may be prepared
by
reacting a precursor compound having a halogen atom in place of the amino
group at the 4-
position with a 5-7 membered ring compound optionally containing an additional
oxygen or
nitrogen atom. Examples of such compounds include, but are not limited to,
morpholine,
piperidine, pyrrolidine, piperazine, thiomorpholine, and the like. Also, this
alternate
procedure may be used to prepare alkyl substituted amino compounds, for
example by
reacting the chloro compound with a mono- or disubstituted amine, such as for
example,
diethylamine, allyl amine, dibutylamine. This reaction takes place readily in
a solvent such
as methylene chloride, for example, in the presence of a tertiary amine. The
precursor
compound having a halogen atom in place of the amino group at the 4-position
may be
prepared by substitution of 6-amino-4-chloro-5-iodopyrimidine for the 4,6-
diamino-5
iodopyrimidine (compound ( 1 ) of Scheme 1 ) and carrying the product forward.
In yet another aspect of the present invention a method of inhibiting
adenosine
kinase is disclosed. In accordance with this method, an adenosine kinase
enzyme is
exposed to an effective inhibiting amount of an adenosine kinase inhibitor
compound of the
present invention. Preferred such compounds for use in the method are the same
as set
forth above. Means for determining an effective inhibiting amount are well
known in the
art.
The adenosine kinase to be inhibited can be located in vitro, in situ or in
vivo.
Where the adenosine kinase is located in vitro, adenosine kinase f s contacted
with the
inhibitor compound, typically by adding the compound to an aqueous solution
containing
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the enzyme, radiolabeled substrate adenosine, magnesium chloride and ATP. The
enzyme
can exist in intact cells or in isolated subcellular fractions containing the
enzyme. The
enzyme is then maintained in the presence of the inhibitor for a period of
time and under
suitable physiological conditions. Means for determining maintenance times are
well known
in the art and depend inter alia on the concentrations of enzyme and the
physiological
conditions. Suitable physiological conditions are those necessary to maintain
adenosine
kinase viability and include temperature, acidity, tonicity and the like.
Inhibition of
adenosine kinase can be performed, by example, according to standard
procedures well
known in the art (Yamada, et al., Comp. Biochem. Physiol. 1982, ~1B: 367-372).
Where the adenosine kinase is located in situ or in vivo, is typically
administered to a
fluid perfusing the tissue containing the enzyme. That fluid can be a
naturally occuring fluid
such as blood or plasma or an artificial fluid such as saline, Ringer's
solution and the like.
A process of inhibiting adenosine kinase in vivo is particularly useful in
mammals such as
humans. Administering an inhibitor compound is typically accomplished by the
parenteral
(e.g., intravenous injection or oral) administration of the compound. The
amount
administered is an effective inhibiting or therapeutic amount.
By a "therapeutically-effective amount" of the compound of the invention is
meant a
sufficient amount of the compound to treat or mitigate adenosine kinase
related disorders or
those diseases or conditions which are ameliorated by adenosine kinase
inhibition and
elevated levels of adenosine, at a reasonable benefit/risk ratio applicable to
any medical
treatment. It will be understood, however, that the total daily usage of the
compounds and
compositions of the present invention is to be decided by the attending
physician within the
scope of sound medical judgment. The specific therapeutically-effective dose
level for any
particular patient will depend upon a variety of factors including the
disorder being treated
and the severity of the disorder; activity of the specific compound employed;
the specific
composition employed; the age, body weight, general health, gender and diet of
the patient;
the time of administration, route of administration, and rate of excretion of
the specific
compound employed; the duration of the treatment; drugs used in combination or
coincidental with specific compound employed; and the like factors well known
in the
medical arts and well within the capabilities of attending physicians.
Compounds of the present invention inhibit adenosine kinase activity in vitro
and in
vivo. In vitro adenosine kinase activity can be measured using any of the
standard
procedures well known in the art. By way of example, cells containing
adenosine kinase,
such as IMR-32 human neuroblastoma cells, are cultured in the presence and
absence of an
inhibitor. Inhibition is measured as the ability to inhibit phosphorylation of
endogenous or
externally applied 14C-adenosine by these cells. The cells can be intact or
broken. The
specificity of adenosine kinase inhibitory activity is determined by studying
the effects of
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inhibitors on adenosine A 1 and A2a receptor binding, adenosine deaminase
activity and
adenosine transport.
Compounds of the present invention are effective in inhibiting adenosine
kinase
activity in vivo. Numerous animal models for studying adenosine kinase
activity and the
affects of inhibiting such activity are well known in the alt. By way of
example, adenosine
kinase inhibitors have been reported to protect rodents (e.g., mice and rats)
from seizures
induced by the subcutaneous administration of pentylenetetrazol (PT'Z).
Typically the
rodents are injected with various doses of a given inhibitor followed at
various times by the
subcutaneous administration of from about 10 to about 500 milligrams per
kilogram of PTZ.
t0 The injected animals are then observed for the onset of seizures.
The compounds of the invention were tested in vivo in the hot plate test of
analgesia
in mammals such as mice. For example, the compounds of examples 55, 103 and
104 in
the procedure described directly below were tested thirty minutes after
pretreatment with the
drugs {30 ~tmol/kg i.p.) for latency to 10th jump (in seconds). The longer the
number of
15 seconds, the more effective the drug at masking the pain felt from the hot
plate. Compound
55 resulted in 132.86 seconds relative to the vehicle alone of 72.76~10.51
seconds.
Compound 103 resulted in 103.29 seconds. Compound 104, when tested, resulted
in an
insignificant score of 62.44 seconds and will be retested in additional models
of pain.
Compounds of the invention are therefore potent pain relievers as well as
adenosine kinase
20 inhibitors as demonstrated in this animal model and the additional assays
described below.
Male CF1 mice (Charles River) of approximately 25-30 g body weight are
pretreated with
25 10 ml/kg of the test compounds, i.p. or p.o, in groups of 8 animals per
dose. At the end of
the pretreatment period, the mice are placed in an Omnitech Electronics
Automated 16
Animal Hot Plate Analgesia Monitor (Columbus, OH; Model AHP16AN) in
individual, 9.8
x 7.2 x 15.3 cm {l x w x h) plastic enclosures on top of a copper plate warmed
to SSoC.
Infared sensors located near the top of each enclosure record beam crossings
that occur as
30 the mice jump off of the heated surface. Latency times for each jump are
automatically
recorded, and latency to both the first and tenth jumps are used for data
analysis. Mice that
do not reach the criteria of 10 jumps by 180 seconds are immediately removed
from the
hotplate to avoid tissue damage, and they are assigned the maximum value of
180 seconds
as their latency to tenth jump.
35 Numerous other animal models of adenosine kinase activity have been
described
[See, e.g., Davies" et al., Biochem. Pharmacol., 33:347-355 (1984); Keil, et
al., Eur. .~.
Pharmacol., 271:37-46 ( 1994); Murray, et al., Drug Development Res., 28:410-
415
( 1993)].
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Numerous inhibitor compounds of the present invention were tested in vitro and
found to inhibit adenosine kinase activity. The results of some representative
studies are
shown below in Table 1 below. The data indicate that the compounds inhibit
adenosine
kinase.
Table 1
Inhibition of Adenosine Kinase by~te_ resentative Compounds of the Invention
Com ound of Exam ICSp
le No. (nM)
3 15
6
9 115
_._ 7
1 11
36 250
38 - 45
55 5
59 117
6
_
63 200
78 25
9 95
103 3
10 8
to .Method of Treating Cerebral Ischemia, Epilepsy,
Nociperception (Nociception) (Pain), Inflammation including
In yet another aspect of the present invention a method of treating cerebral
ischemia,
epilepsy, nocipercepdon or nociception, pain, inflammation including
conditions such as
septic shock due to sepsis infection in a human or lower mammal is disclosed,
comprising
administering to the mammal a therapeutically effective amount of a compound.
Alterations in cellular adenosine kinase activity have been observed in
certain
disorders. Adenosine kinase activity was found to be decreased, relative to
normal liver, in
a variety of rat hepatomas: activity of the enzyme giving a negative
correlation with tumor
growth rate (Jackson, et al., Br. J. Cancer, 1978, :37: 701-713). Adenosine
kinase activity
was also diminished in regenerating liver after partial hepatectomy in
experimental animals
(Jackson, et al., Br. J. Cancer, 1978, 37: 701-713;1. Erythrocyte Adenosine
kinase activity
was found to be diminished in patients with gout (;Nishizawa, et al., Clin.
Chim. Acta 1976,
67: 15-20). Lymphocyte adenosine kinase activity was decreased in patients
infected with
the human immunodeficiency virus (HIV) exhibiting symptoms of AIDS, and
increased in
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asymptomatic HIV-seropositive and HIV-seronegative high-risk subjects,
compared to
normal healthy controls (Renouf, et al., Cliia. Chem. 1989, 35: 1478-1481). It
has been
suggested that measurement of adenosine ldnase activity may prove useful in
monitoring the
clinical progress of patients with HIV infection (Renouf, et al., Clin. Chem.
1989, 35:
1478-1481). Sepsis infection may lead to a systemic inflammatory syndrome
(SIRS),
characterized by an increase in cytokine production, neutrophil accumulation,
hemodynamic
effects, and tissue damage or death. The ability of adenosine kinase inhibitor
to elevate
adenosine levels in tissues has been demonstrated to ameliorate syndrome
symptoms, due to
the know anti-inflammatory effects of adenosine. (Firestein, et al., J. of
Immunology,
1994, pp. 5853-5859). The ability of adenosine kinase inhibitors to elevate
adenosine levels
is expected to alleviate pain states, since it has been demonstrated that
administration of
adenosine or its analogs results in antinociception or antinociperception.
(Swaynok, et al.,
Neuroscience, 1989, 32: No. 3, pp. 557-569).
The compounds and processes of the present invention will be better understood
in
connection with the following Examples, which are intended as an illustration
of and not a
limitation upon the scope of the invention.
E am a 1
4-amino-6- henvl-7-lp-dimeth lamino~hen~pyridof2 3-dlRyrimidine
A sample of 4,6-diamino-5-(2-phenylethenyl)pyrimidine ( 1 SO mg) was suspended
in
10 mL of phenylether with 1.2 eq of 4-{dimethylamino)benzaldehyde (the "R4"
Reagent)
and 1.5 g~of 4A molecular sieves. The solution was heated to 170 °C for
4 hours, then
cooled, and the solvent was removed. The residue was purified by column
chromatography
to give the title compound. IR (KBr) 3325, 1589, 1555, 1400, 1340, 1196, 819
cm-1; MS
m/z 342 [M+H]+.
The 4,6-diamino-5-(2-phenylethenyl)pyrimidine was prepared as follows:
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1~. 5-iodo-4.6-diaminop,Srrimidine
4,6-Diaminopyrimidine hemisulfate monohydrate (26.13 g, 147.5 mmol, Aldrich)
and K2C03 (30.58 g, 221.3 mmol) were suspended in water (400 mL). To this
suspension
was added a solution~of iodine (41.19g, 162.3 mmol) in DMF (100 mL). The
mixture was
heated at 45 °C for 23 hours. After cooling, a 2 M solution of Na2S2O3
(15 mL) was added
to quench the excess iodine. The white product was then collected, washed with
water (3 x
20 mL) and dried under high vacuum to yield 33.1 g of the title compound
(90%).
l b 2-phenyllethenylboronic acid (the "R3" Reaeent)
Phenylacetylene (5 mmol, Aldrich) was dissolved in 5 mL of dry THF and
catecholborane (5 mL, 1 M in THF, Aldrich) was added dropwise at 0 °C.
The solution was
heated to reflux for 1.5 hours, and the solvent was removed under vacuum. The
solution
was quenched with 1 M HCl ( 10 mL), and this solution is taken directly to the
next step.
I c 4 6-diamino-5-(2-phenylethenyl~wrimidine
To a solution of 5-iodo-4,6-diaminopyrimidine ( 1 mmol, from step 1 a above)
in 50
mL of dioxane , 2-phenylethenylboronic acid (5 mmol), 5% of Pd(PPh3)4, and 1M
Na2C03
( 10 mL) were added. The reaction mixture was heated for 12 hours. The solvent
was
removed under vacuum, and the residue was diluted with water and extracted
with CH2Cl2
(3 x 30 mL). The organic layer was concentrated under reduced pressure, and
the residue
was dried under high vacuum. The crude mixture was subjected to column
chromatography
(using 5% MeOH/CH2C12 as eluant) to give the title compound. MS m/z: 213
(M+H)+.
Exam les 2-107
Following the procedures of Example 1, except substituting the reagents given
in
Table 1 below for the R4 and R3 Reagents of Example 1, the compounds of
Examples 2-107
were prepared.
Table 1
Examples 2-1127
Ex. Name R4 Reagent- R3 Reagent- data
No. 7 osition~ 6- osition)
2 4-amino-6-(4-methylphenyl)-7-4-(dimethylamino)-2-(4-methylphenyl)-IR
(KBr) 3360,
(4- benzaldehyde ethenyl-boronic1660, 1600,
acid 1185,
(dimethylamino)phenyl)pyrido[ cm-1 ~ MS
m/z 356
2,3-d]pyrimidine
M+H +
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WO 98/46603 PCT/US98/04127
3 4-amino-6-(4- 4-(dimethylamino)-2-(4- IR (microscope)
(dimethylamino)phenyl)-7-(4-benzaldehyde dimethylaminophen3325. 1608,
1589,
(dimethylamino)phenyl)pyrido[ yl)-ethenyl-boronic1560. 1520,
1400,
2.3-d]pyrimidine acid 1358, 1340,
1196,
818 cm-1;
MS m/z
385 M+H +
4 4-amino-6-(4-methylphenyl)-7-benzaldehyde 2-(4-methylphenyl)-IR
(microscope)
phenylpyrido[2,3-d]pyrimidine ethenyl-boronic3325, 1659,
acid 1553,
1340, 1340,
821
cm-1; MS m/z
313
M+H +
5 4-amino-6-(4-methylphenyl)-7-4- 2-(4-methylphenyl)-IR
(microscope)
(4-bromophenyl)pyrido[2,3-bromobenzaldehydeethenyl-boronic3325. 1600,
acid 1553,
d]pyrimidine 1340. 1340,
818
cm-I; MS m/z
391
M+H +
6 4-amino-6-(4- pyridine-4- 2-(4- IR (microscope)
(dimethylamino)phenyl}-7-(4-carboxaldehydedimethylaminophen3320, 1608,
1560,
pyridinyl)pyrido[2.3- yl)-ethenyl-boronic1521. 1410,
1344.
d]pyrimidine ~d 818 cm-I;
MS m1z
343 M+H +
7 4-amino-6-(4- 4- 2-(4- IR (microscope)
(dimethylamino)phenyl)-7-(4-bromobenzaldehydedimethylaminophen3320. 1606,
1562,
bromophenyl)pyrido[2,3- yl)-ethenyl-boronic1547, 1520,
1340,
d]pyrimidine ~d 1010. 818
cm-I;
MS m/z 420
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-(5- 2-(4-methylphenyl)-IR 3360,
3160,
(4-(5- pyrimidinyl)benzaldethenyl-boronic1600, 1555,
acid 1410,
pyrimidinyl)phenyl)pyrido[2,3-ehyde 1345, 820;
MS m/z
d]pyrimidine 391 (M+H +
9 4-amino-6-(4-methylphenyl)-7-4-(2-(2- 2-(4-methylphenyl)-IR 3400,
3320,
(4-(2-(2- pyridinyl)ethenyl)beethenyl-boronic3160. 3040.
acid 1595,
pyridinyl)ethenyl)phenyl)pyridonzalckhyde 1560. 1340;
MS
[2,3-d]pyrimidine
m/z 416 M+H
+
10 4-amino-6-(4-methylphenyl)-7-3- 2-(4-methylphenyi)-IR 3320.
3360,
(3-pyridinyl)pyrido[2,3-pyridinecarboxaldehethenyi-boronic3040. 1640,
acid 1550,
d]pyrimidine yde 1340. 815;
MS mlz
314 (M+H)+.
11 4-amino-6-(4-methylphenyl)-7-3- 2-(4-methylphenyl)-IR 3440,
3320,
(thiophen-3-yl)pyrido[2,3-thiophenecarboxaldeethenyl-boronic3160, 3100,
acid 1600,
d]pyrimidine hyde 1555, 1335;
MS
ml z 319 M+H
+
12 4-amino-6-(4-methyiphenyl)-7-2- 2-(4-methylphenyl)-IR 3460.
3360,
(thiophen-2-yl)pyrido[2,3-thiophenecarboxaldeethenyl-boronic3310, 3100,
acid 1600,
d]pyrimidine hyde 1555, 1425;
MS
m/z 319 (M+H
+
13 4-amino-6-(4-methylphenyl)-7-2- 2-(4-methylphenyl)-IR 3440,
3320,
(2-pyridinyl)pyrido[2,3-pyridinecarbozaldehethenyi-boronic3170, 1640,
acid 1600,
d]pyrimidine yde 1555, 1340;
MS
m/z 314 M+H
+
-30-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 PGT/US98/0412~
14 4-amino-6-(4-methylphenyi)-7-3,4- 2-(4-methylphenyl)-IR 3365.
3120,
(3.4- Methylenedioxybenzethenyl-boronic1600, 1555,
acid 1440,
methylenedioxyphenyl)pyrido[2aldehyde 1250, 1040:
MS
,3-d]pytimidine m/z 357 M+H
+
15 4-amino-6-butyl-7-(thiophen-2-2- 1-hexenyl-boronicIR 3320,
3160,
yl)pyrido[2,3-d]pyrimidinethiophenecarboxaldeacid 2955, 2860,
1640,
hyde 1560, 1335;
MS
m/z 285 M+H
+
16 4-amino-6-butyl-7-(thiophen-3-3- 1-hexenyl-boronicIR 3300,
3070,
yl)pyrido[2,3-d]pyrimidinethiophenecarboxaldeacid 2950, 2850,
1600,
hyde 1565, 1330;
MS
m/z 285 M+H
+
17 4-amino-6-(4-methylphenyl)-7-5-bromothiophen-'.>.-2-(4-methylphenyl)-IR
3450,
3300,
(S-bromothiophen-2-carboxaldehydeethenyl-boronic3100, 1640,
acid 1600,
yl)pyrido[2,3-d]pyrimidine 1555, 1425:
MS
mlz 397/399
M+H +
18 4-amino-6-(4-methylphenyl)-7-5-methylthiophen-2-2-(4-methylphenyl)-IR
3460,
3380,
(5-methylthiophen-2-carbozaldehydeethenyl-boronic3300, 3150.
acid 1640,
yl)pyrido[2,3-d]pyrimidine 1555, 1445:
MS
m/z 333 M+H
+
19 4-amino-6-(4-methylphenyl)-7-4- 2-(4-methylphenyl)-IR 3440,
3320,
(4- (trifluoromethyl)bc:nethenyl-boronic3180, 1555.
acid 1490.
(trifluoromethoxy)phenyl)pyridzaldehy~ 1340, 820;
MS m/.
0[2,3-d]pyrimidine 397 M+ +
2 4-amino-6-(4-methylphenyl)-7-3- 2-(4-methylphenyl)-IR 3400,
0 3180,
(3-phenoxyphenyl)pyrido[2,3-ph~oxybenzaldehydethenyl-boronic3050, 1555,
acid 1340,
d]pyrimidine a 1255, 820;
MS m/z
405 M+H +
21 4-amino-6-(4-methylphenyl)-7-S-vitro-thiophen-2-2-(4-methylphenyl)-IR
3380.
3100,
(5-nitrothiophen-2-carboxaldehydeethenyl-boronic1595, 1550,
acid 1330,
yl)pyrido[2,3-d]pyrimidine 1260. 815;
MS m/z
364 (M+ +
2 4-amino-6-(4-methylphenyl)-7-4-bromo-thiophen-2-(4-methylphenyl)-IR 3320.
2 3100,
(4-bromothiophen-2-2-ca~oxaldehydeethenyl-boronic1595, 1555,
acid 141 S,
yi)pyrido[2,3-d]pyrimidine 1340, 820;
MS m/z
397, 399
M+H +
2 4-amino-6-(4-methylphenyl}-7-3-methyl-thiophen-2-(4-methylphenyl)-IR 3300,
3 3060,
(3-methylthiophen-2-2~arboxaldehydeethenyl-boronic1600, 1550,
acid 1450.
yl)pyrido[2,3-d]pyrimidine 1335, 820;
MS m/z
333 M+ +
2 4-amino-6-(4-methylphenyl)-7-furan-2- 2-(4-methylphenyl)-IR 3430,
4 3300,
(furan-2-yl)pyrido[23-carboxaldehydeethenyl-boronic3170, 1630,
acid 1560,
d]pyrimidine 1450, 1340;
MS
m/z 303 M+H
+
2 4-amino-6-(4-methylphenyl)-7-fiuan-3- 2-(4-methylphenyl)-IIt 3360.
S 3140,
(furan-3-yi)pyrido[2,3-carboxaldehydeethenyl-boronic1655, 1605,
acid 1555,
d]pyrimidine 1340, 1165;
MS
ml z 303
M+H +
-31-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 PCT/US98/04127
2 4-amino-6-(4-methylphenyl)-7-5-methylfman-2-2-(4-methylphenyl)-IR 3440,
3180,
6
{5-methyl-ftuan-2- carboxaldehydeethenyl-boronic1630, 16()D.
acid 1555,
yl)pyrido(2,3-d]pyrimidine 1335, 820;
MS mlz
317 M+ +
2 4-amino-6-(4-(2- thiophen-2- 2-(4-(2- IR 3460, 3320,
7
propyl)phenyl)-7-(thiophen-2-carboxaldehydepropyl)phenyl)-3160, 2960,
1600,
yl)pyrido[2,3-d]pyrimidine ethenyl-boronic1555, 1425;
acid MS
m/z 347 M+H
+
2 4-amino-6-(4-(2- 5-nitro-thiophen-2-2-(4-(2- IR 3380, 3160,
8
propyl)phenyl)-7-(5-carboxaldehydepropyl)phenyl)-2960, 1635,
1600,
nitrothiophen-2-yl)pyrido[2,3- ethenyl-boronic1555, 1330;
acid MS
d]pyrimidine m/z 392 M+H
+
2 4-amino-6-(4-methylphenyl)-7-5-vitro-thiophen-2-2-(4-methylphenyl)-IR
3330, 3160,
9
(5-nitrothiophen-2-carboxaldehydeethenyl-boronic1630, 1600,
acid 1555,
yl)pyrido(2,3-d]pyrimidine 1350, 810;
MS m/z
348 M+
3 4-amino-6-(4- thiophen-2- 2-(4- IR 3440, 3160,
0
(dimethyiamino)phenyl)-7-carboxaldehyde(dimethylamino)phe1610, 1555.
1525,
(thiophen-2-yl)pyrido[2,3- nyl)-ethenyl-boronic1340, 820;
MS m/z
d)pyrimidine ~ 348 M+H +
31 4-amino-6-(3,4- thiophen-2- 2-(3,4- IR 3420. 3080.
dimethozyphenyl)-7-(thiophen-carboxaldehydedimethoxyphenyl)-1600, 1560,
1515,
2-yI)pyrido[2,3-d]pyrimidine ethenyl-boronic1425, 1340;
acid MS
m/z 365 M+H
+
3 4-amino-6-(3,4- 5-nitro-thiophen-2-2-(3,4- IR 3420, 2840,
2
dimethozyphenyl)-7-(5-carboxaldehydedimethoxyphenyl)-1600, 1555,
1515,
nitrothiophen-2-yl)pyrido[2.3- ethenyl-boronic1335, 1255;
acid MS
d]pyrimidine m/z 410 M+H
+
3 4-amino-6-hexyl-7-(4-4-(dimethyiamino)-1-octenyl-boronicIR 3320, 3100,
3
(dimethylamino)phenyl)pyrido[benzaldehydeacid 2920, 2850,
1600,
2,3-d]pyrimidine 1560, 1335;
MS
m/z 350 M+H
+
3 4-amino-6-hexyl-7-(thiophen-2-thiophen-2- 1-octenyl-boronicIR 3320, 3160,
4
yl)pyrido[2,3-d]pyrimidinecarboxaldehy~acid 2920, 2840,
1600,
1560, 1425;
MS
mlz 313 (M+H
+
3 4-amino-6-(2-methyl-2-propyl)-thiophen-2- 3,3-dimethyl-I-IR 3400, 3320.
5
7-(thiophen-2-yl)pyrido[2.3-carboxaldehydebutenyl-boronic3180, IR 2960,
acid
d)pyrimidine 1640, 1565,
1335;
MS ml z 285
M+H +
3 4-amino-6-(4-(2- 4-(dimethyiamino)-2-(4-(2- IR 3600-3250,
6
propyl)phenyl)-7-(4-benzaldehy~ propyl)phenyl)-2955, 1590,
1555,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1400. 1340,
acid 1195,
2,3-d)Pyrimidine 815;
MS m/z 384
(M+H)+.
-32-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 PCTIUS98/04127
3 4-amino-6-(4-propylphenyl)-7-4-(dimethylamino)-2-(4-propylphenyl)-IR 3520-
3250.
7
(4- benzaldehydeethenyl-boronic2960, 1590,
acid 1555.
(dimethyiamino)phenyl)pyrido[ 1400, 1340,
1195,
2,3-d]pyrimidine 815;
MS m/z 384
M+H +
3 4-amino-6-(3,4- 4-(dimethylamino)-2-(3,4- IR 3320, 3240-
8
dimethoxyphenyl}-7-(4-benzaldehydedimethoxyphenyl~2760, 1590,
1560,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1510, 1515,
acid 1340,
2,3-d]pyrimidine g20;
MS mlz 384
M+H +
3 4-amino-6-(3-methoxyphenyl)-4-(dimethylamino)-2-(3- IR 3365, 3320,
9
7-(4- benzaldehydemethoxyphenyl)-3250-2780,
1660,
(dimethylamino)phenyl)pyt;do[ ethenyl-boronic1590, 1560.
acid 1460,
2,3-d]pyrimidine 1400, 1200.
820;
MS m/z 402
M+H +
4 4-amino-6-(3-bromophenyl~7-4-(dimethylamino)-2-(3-bromophenyl)-IR 3400-
3250.
0
(4- benTaldehydeethenyl-boronic3250-2840,
acid 1660.
(dimethylamino)phenyl)pyrido[ 1590, 1560.
1340,
2.3-d]pyrimidine 1200, 820;
MS m/z 420
M+H +
41 4-amino-6-(3-fluorophenyl)-7-4-(dimethylamino)-2-(3-fluorophenyl)-IR 3520-
2800.
(4- benzaldehydeethenyl-boronic1645, 1610,
acid 1590.
(dimethylamino)phenyl)pyrido[ 1560, 1525,
1400,
2,3-d]pyrimidine 1340, 1200.
820;
MS m/z 360
M+H +
4 4-amino-6-(3- 4-(dimethylamino)-2-(3- IR 3560, 3520,
2
trifluoromethylphenyl)-7-(4-benzaldehydetrifluoromethylphen3240-2840,
1660,
(dimethylamino)phenyl)pyrido[ yl)-ethenyl-boronic1590, 1560.
1400,
2,3-d]pyrimidine acid 1340, 1160,
1120,
810, 700;
MS m/z 410
M+H +
4 4-amino-6-(3-chlorophenyl~7-4-(dimethylamino)-2-(3-chlorophenyl)-IR 3500-
3280,
3
(4- benzaldehydeethenyl-boronic3200-2840,
acid 1660,
(dimethylamino)phenyl)pyrido[ 1590, 1560,
1395,
2,3-d]PY~~ 1370, 1340,
1200,
820;
MS mlz 376
M+H +
44 4-amino-6-(3,5- 4-(dimethylamino)-2-(3,5- IR 3560-3280.
dichlorophenyl~7-(4-benzaldehydedichlorophenyl~3240-3300,
1640,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1590, 1560,
acid 1400,
2,3-d]pyrimidine 1365, 1340,
1195,
820, 800;
MS m/z 411
M+H +
-33-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 pCTIUS98/04127
4 4-amino-6-(3,4- 4-(dimethylamino)-2-(3,4- IR 3600-3280,
5
methylenedioxyphenyl)-7-(4-bennldehyde methylenedioxyphen3240-3000,
1595,
(dimethylamino)phenyl)pyrido[ yl}-ethenyl-boronic1560, 1400,
1195.
2,3-d]pyrimidine acid 1040, 815:
MS min
386 M+ +
4 4-amino-6-(3,4- thiophen-2- 2-(3,4- 1R 3430, 3300,
6
methylenedioxyphenylr7-carboxaldehydemethylenedioxyphen3170, 1630,
1595,
(thiophen-2-yl)pyrido[2,3- yl)-ethenyl-boronic1575, 1450,
1425,
d]pyrimidine acid 1035, 820:
MS mlz 349
M+H +
4 4-amino-6-(3- 4-(dimethylamino)-2-(3- IR 3360. 3320,
7
methoxycarbonylphenyl)-7-(4-benzaldehyde methoxycarbonylph3200-3000.1720,
(dimethylamino)phenyl)pyrido[ enyl)-ethenyl-1660, 1595,
1560,
2.3-d]pyrimidine boronic acid1400, 1340,
1200,
820;
MS mlz 400
M+H +
4 4-amino-6-(3-(2- 4-(dimethylamino)-2-(3-(2- IR 3500-3280,
8
propyl)phenyl)-7-(4-benzaldehyde propyl)phenyl)-3200-3000.2960,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1590. 1555,
acid 1395.
2,3-d]pyrimidine 1340. 1195;
MS ml.
384 M+ +
4 4-amino-6-(4-(2-methyl-2-4-(dimethylamino)-2-(4-(2-methyl-2-1R 3520-3280,
9
propyl)phenyl)-7-(4-benzaldehyde propyl)phenyl}-3180. 2960,
1590,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1555. 1340,
acid 1195,
2,3-d]pyrimidine 820;
MS ml_ 398
M+H +
5 4-amino-6-(4-fluorophenyl)-7-4-(dimethylamino)-2-(4-fluorophenyl)-IR 3490,
3320,
0
(4- benzaldehyde ethenyl-boronic3200-3000,
acid 1590,
(dimethylamino)phenyt)pyrido[ 1555, 1400,
1340.
2,3-d]pvtimidine 1195, 820;
MS mlz 360
(M+H)+.
51 4-amino-6-(4-methoxyphenyl)-4-(dimethylamino)-2-(4- IR 3370. 3320,
7-(4- benz~ldehyde methoxyphenyl)-3200-3000,
1660,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1590, 1555,
acid 1400,
2,3-d]pyrimidine 1340, 1250,
1195,
815;
MS ml: 372
M+H +
5 4-amino-6-(3- 4-(dimethylamino)-2-(3- 1R 3360, 3320,
2
(phenyLnethoxy)phenyl)-7-(4-benzaldehyde (phenylmethoxy)phe3200-3000,
1655.
(dimethylamino)phenyl)pyrido[ nyl)-ethenyl-boronic1590. 1560,
1400,
2,3-d]pyrimidine acid 1195.820;
MS mlz 448
M+H +
-34-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 PCT/US98/04127
4-amino-6-(4-chlorophenyl)-7-4-(dimethyIamino)-2-(4-chlorophenyI)-IR 3480-
3320,
3
(4- benzaldehydeethenyl-boronic3200-3020,
acid 1590,
(dimethylamino)phenyl)pyrido[ 1550, 1410,
1340.
2,3-d]pyrimidine 1195, 815:
MS m/z 376
M+H +
5 4-amino-6-(3-fluoro-4-4-(dimethylamino)-2-(3-fluoro~-IR 3360. 3160-
4
methylphenyl)-7-(4-benzaldehydemethylphenyl)-3000, 1660,
1590,
(dimethylamino)phenyl)pyrido[ ethenyl-boronic1555, 1340,
acid 1200,
2,3-d]pyrimidine 820;
MS m/z 374
M+H +
5 4-amino-6-(3-fluoro-4-thiophen-2- 2-(3-fluoro-4-IR 3600-3300,
5
methylphenyl)-7-(thiophen-2-carboxaldehydemethylphenyl)-3200.3020.1620,
yl)pyrido[2,3-d]pyrimidine ethenyl-boronic1415:
acid
MS m/z 337
M+H +
5 4-amino-6-(3-phenylpropyl)-7-4-methoxy- 5-phenyl-1- NMR (CDC13)
6 8
(4-methoayphenyl)pyrido[2,3-benzaldehydepentenyl-boronicg,70
(s.lH), 8.06
- d]pyrimidine acid .
(s,lH), 7.53
(d,
J=9Hz, 2H),
7.22
(m, 3H), 7.06
(d,
J=BHz, 2H),
6.94
(d. J=9Hz,
2H),
6.19 (s, br,
2H),
3.88 (s, 3H),
2.88
(m, 2H), 2.57
(m,
2H), 1.88
(m, 2H);
MS m/z 37i
M+H +
5 4-amino-6-(3-phenylpropyl)-7-4-(dimethylamino)--5-phenyl-1- NMR (CDCl3)
7 8
~~yde ~denyl-boronic8.73 (s. 1H),
7.88
(dimethylamino)phenyl)pyrido[ (s.lH), 7.58
(d,
2,3-d]pyrimidine J=BHz, 2H),
7.22
(in. 3H),
7.10 (d,
J=8Hz. 2H).
6.73
(d. J=9Hz.
2H),
5.78 (s, br.
2H),
3.04 (s. 6H).
2.96
(m, 2H). 2.61
(t,
J=8Hz, 2H),
1.91
(m, 2H);
MS m/z 384
M+H +
58 4-amino-6-(2-phenylethyl)-7-(4-4-(dimethylamino)-4-phenyl-1-butenyl-NMR
(CDC13)
b
(dimethylaminomhenyl)pyrido[benzaldehydeboronic acid 8.75 (s, 1H)
7.69
2,3-d]pyrimidine ,
(s, 1H), 7.65
(m,
2H), 7.21
(m, 3H),
7.04 (m, 2H),
6.79
(m, 2H), 5.57
(s,
br, 2H), 3.25
(m,
2H), 3.04
(s, 6H).
2.85 (m. 2H);
MS m/z 370
M+H +
-35-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 PCT/US98/04127
59 4-amino-6-(phenylmethyl)-7-(4-4-(dimethylamino)-3-phenyl-1- NMR (CDC13)
S
(dimethylamino)phenyl)pyrido[benzaldehydepropenyl-boronicg,74 (s. 1H),
7.74
2.3-d]pyrimidine acid
(s, 1H), 7.65
(d,
J=9Hz, 2H),
7.30
(m, 3H), 7.10
(m,
2H), 6.74
(d,
J=9Hz, 2H),
5.64
(s, br, 2H),
4.29 (s,
2H), 3.02
(s, 6H);
MS m/z 356
M+H +
6 4-amino-6-(cyclohexylmethyl)-4-{dimethylamino)-3-cyclohexyl-1-NMR (CDC13)
0 b
~~~y~ Qd enyl-boronicg,75 (s, 1H).
7.90
(dimethylamino)phenyl)pyrido[ (s, 1H), 7.59
(d,
2,3-d]pyrimidine J=9Hz, 2H),
6.76
(d. J=9Hz,
2H),
5.82 (s, br.
2H),
3.03 (s, 6H).
2.83
(d, J=7Hz,
2H),
1.70-1.40
(m, 6H).
1.07 (m. 3H),
0.83
(m, 2H);
MS m/z 362
M+H +
61 4-amino-6-butyl-7-(4-4-(dimethyla~nino)-1-hexenyl-boronicNMR (CDCI3)
S
(dimethylamino)phenyl)pyrido[benzaldehydeacid 8.74 (s. 1H),
7.96
2.3-d]pyrimidine
(s, 1 H),
7.62 (d,
J=9Hz, 2H).
6.77
(d, J=9Hz,
2H),
5.86 (s, 2H).
3.04
(s, 6H), 2.91
(m,
2H), 1.57
(m,2H),
1.32 (sextet,
J=7Hz,
2H), 0.87
(t, J=7Hz,
3H);
MS m/z 322
(M+H +
6 4-amino-b-pentyl-7-(4-4-(dimethylamino)-1-heptenyl-boronicNMR (DMSO-db
2 ) b
(dimethylamino)phenyl)pyrido[benzaldehydeacid 8.53 (s, 1H).
8.45
2,3-d]pyrimidine
(s, 1H), 7.47
(d,
J=8Hz, 2H),
6.82
(d, J=8Hz.
2H),
3.34 (s, 1H),
3.32
(s, 1H), 2.99
(s,
6H), 2.81
(m, 2H),
1.58 (m, 2H).
1.23
(m, 4H), 0.82
(m,
3H);
MS mlz 336
M+H +
-36-
SUBSTITUTE SHEET (RULE 26~
CA 02287465 1999-10-14
WO 98/46603 PGT/US98/04127
63 4-amino-6-(2-methylpropyi)-7-4-(dimethylamino)-4-methyl-1- NMR (CDCl3)
8
(4- benzaldehydepentenyl-boronic8.76 (s.
1H), 7.88
(dimethylamino)phenyl)pyrido[ acid (s, 1H),
7.61 (d,
2,3-d]pyrimidine J=9Hz, 2H),
6.77
(d. J=9Hz,
2H).
5.76 (s,
br, 2H),
3.03 (s,
6H). 2.84
(d, J=7Hz,
2H),
1.78 (m,
1H}, 0.78
(d. J=6Hz.
6H);
MS mlz 322
M+H +
6 4-amino-6-propyl-7-(4-4-(dimethylamino)-1-pentenyl-boronicNMR (DMSO-d~
4 ) b
(dimethylamino)phenyl)pyrido[benzaldehydeacid 8.52 (s.
1H), 8.45
2,3-d]pyrimidine
(s, 1H),
7.90 (s,
br,
2H), 7.48
(d,
J=8Hz. 2H).
6.82
(d. J=8Hz,
2H),
2.99 (s,
6H). 2.80
(m, 2H),
1.60
(sextet.
J=7Hz, 2H),
0.85 (t,
J=7Hz. 3H);
MS mlz 308
M+H +
6 4-amino-6-(3-cyanopropyl)-7-4-(dimethylamino)-5-cyano- 1-pentenyl-NMR
(DMSO-db
) 8
(4- benzaldehydeboronic acid 8.56 (s,
1H), 8.47
(dimethylamino}phenyl)pyrido[
(s, 1H),
7.94 (s,
br,
2,3-d]pyrimidine 2H). 7.50
(d,
J=9Hz, 2H).
6.83
(d, J=9Hz.
2H),
3.00 (s,
6H), 2.93
(m, 2H),
2.50 (m,
. 2H), 1.90
(m, 2H);
MS m1z 333
M+H +
6 4-amino-6-(3-nitrophenyl)-7-(4-4-(dimethylamino)-2-(3- IR
6
(dimethylamino)phenyl)pyrido[benzaldehydenitrophenyl)ethenyl3360.3100,1590,15
2,3-d]pyrimidine boronic acid 60
MS m/z 387
M+H +
6 4-amino-6-pentyl-7-(thiophen-thiophen-2- 1-heptenyl-boronic'dR
7
2-yl)pytido[2,3-d]pyrimidinecarbozaldehyde 3320.3100,1560,14
30
MS mlz 299
M+H +
.
6 4-amino-6-(3- 4-(dimethylamino}-5-cyano-l-pentenyl-IR
8
carbozamidopropyl~7-(4-benzaidehydeboronicacid 3325,3120,1660,15
(dimethylamino)phenyl)pyrido[ 95
2,3-d]pyrimidine MS mlz 351
M+H +
6 4-amino-6-((4- thiophen-2- 2-(4- IR
9
methozyphenylhnethyl)-7-carboxa~ttydemethoxyphenyl)-3360,3100,1605,15
(thiophen-2-yl)pyrido[2.3- propenyl boronic65
d]pyrimidine acid MS m/z 349
'
M+H +
-37-
SUBSTITUTE SHEET (RULE 28)
CA 02287465 1999-10-14
WO 98/46603 PCT/US98/04127
7 4-amino-6-((3- thiophen-2- 2-(3-bromophenyl)-IR
0
bromophenyl)methyl)-7-carboxaldehydepropenyl 3440,3120,1605,15
boronic
(thiophen-2-yi)pyrido[2,3- acid 65
d]pyrimidine MS mi. 397/399
M+H +
? 4-amino-6-((4-(2- thiophen-2- 2-(4-(2- IR
1
propyl)phenyl)methyl)-7-carboxaldehydepropyl)phenyl)-3440.3080,1600,15
(thiophen-2-yl)pyrido[2,3-
propenyl 60
boronic
d]pyrimidine acid MS ml~ 361
M+H +
7 4-amino-6-({4- 4-isopropyl- 2-(4- IR
2
methoxyphenyl)methyl)-7-(4-benzaldehyde methoxyphenyl)-3360.3120,1565,15
{2-propyl)phenyl)pyrido[2,3- propenyl 10
boronic
d]pyrimidine acid MS m/z 385
M+H '~
7 4-amino-6-((4- thiophen-2- 2-(4-bromophenyl)-IR
3
bromophenyl)methyl)-7-carboxaldehyckpiopenyl 3440.3160.1625,15
boronic
(thiophen-2-yl)pyrido[2,3- acid 60
d]pyrimidine MS n_ 397/399
M+H)+.
7 4-amino-6-((3- thiophen-2- 2-(3-fiuorophenyl)-1R
4
fluorophenyl)methyl)-7-carbox<~ldehydepropenyl 3320.3 i60,1600,I5
boronic
(thiophen-2-yl)pyrido[2,3- acid 60
d]pyrimidine MS m/. 337
M+H +
7 4-amino-6-((4- thiazole-2- 2-(4-bromophenyl)-IR
5
bromophenyl)methyl)-7-carboxaldehydepropenyl 3450,3100,1635,15
boronic
(thiazole-2-yl)pyrido[2,3-
acid 60
d]pyrimidine MS ml= 398/400
M+H)+.
7 4-amino-6-((3- thiophen-2- 2-(3- IR
6
methoxyphenyl)methyl)-7-c~~u~boxaldehydemethoxyphenyl)-3450,3150,1600,15
(thiophen-2-yl)pyrido[2,3-
propenyl 60
boronic
d]pyrimidine acid MS m/z 349
M+H +
7 4-amino-6-(phenylmethyl)-7-thiophen-2- 2-phenyl-1-propenylIR
7
(thiophen-2-yl)pyrido(2,3-carboxaldehydeboronic acid3390.3110,1605,1
S
d]pyrimidine 65
MS m/z 319
M+H +
-
7 4-amino-6-((3- 4-(dimethylamino)-2-(3- IR
8
methozyphenyl)methyl)-7-(4-benzaldehyde methoxyphenyl)-3310,3080,1600,15
(dimethylamino)phenyl)pyrido( propenyl 65
bionic
2,3-d]pyrimidine acid MS m/z 386
M+H +
7 4-amino-6-(4-methylphenyl)-7-4-(trifluoromethyl)-2-(4-methylphenyl)-IR
9
(4- ben~aldehyde ethenyl boronic3230,1325,820;M
acid
(trifluoromethyl)phenyl)pyrido[ S m/z 381
2,3-dlpyrimidine M+H +
8 4-amino-6-(4-methyiphenyl)-7-4-methyl- 2-(4-methylphenyl)-IR
0
(4-methylphenyl)pyrido[2,3-benzaldehyde ethenyl boronic3450,1449,1340,8
acid
d]pyrimidine 20;MS m/z
327
M+H +
-38-
SUBSTITUTE SHEET (RULE 26)
CA 02287465 1999-10-14
WO 98/46603 PGT/ITS98/04127
81 4-amino-6-(4-methylphenyl)-7-4-methoxy- 2-(4-methylphenyl)-IR
(4-methoxyphenyl)pyrido[2,3-benzaldehydeethenyl boronic3375,1600,820;M
acid
d]pyrimidine S m/z 343
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-ethyl-benzaldehyde;2-(4-methylphenyl)-IR
2
(4-ethylphenyl)pyrido[2,3- ethenyl boronic3340,1558.1340,8
acid
d]pyrimidine 20;MS m/z
341
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-cyano- 2-(4-methylphenyl)-IR
3
(4-cyanophenyl)pyrido[2,3-benzaldehydeethenyl boronic3320,1560.820;M
acid
d]pyrimidine S m/z 338
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-acetamido-2-(4-methylphenyl)-IR
4
(4-acetamidophenyl)pyrido[2,3-benzaldehydeethenyl boronic3325.1520.820;M
acid
d]pyrimidine S m/z 370
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-phenoxy- 2-(4-methylphenyl)-IR
(4-phenoxyphenyl)pyrido[2.3-benz~ldehy~ ethenyl boronic3340,1550.1240,7
acid
d]pyrimidine SO:MS m/z
405
M+H +
8 4-amino-6-(4-methyiphenyl)-7-4-vitro-benzaldehyde2-(4-methylphenyl)-IR
6
(4-nitrophenyl)pyrido[2,3- ethenyl boronic3390.1340.850:M
acid
d]pyrimidine S m/z 358
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-fluoro- 2-(4-methylphenyl)-IR
7
(4-fluorophenyl)pyrido[2,3-benT.~ldehydeethenyl boronic3320,1550,1340.8
acid
d]pyrimidine 40;MS m/z
331
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-chloro- 2-(4-methylphenyi)-IR
8
(4-chlorophenyl)pyrido[2,3-benzaldehydeethenyi boronic3340,1550,1340,9
acid
d]pyrimidine lO;MS m/z
347
M+H +
8 4-amino-6-(4-methylphenyl)-7-4-amino- 2-(4-methylphenyl)-IR
9
(4-aminophenyl)pyrido[2,3-benzatdehydeethenyl boronic3325,1550,820;M
acid
d]pyrimidine S m/z 328
M+H +
9 4-amino-6-(4-methylphenyl)-7-4-methylthio-2-(4-methylphenyl)-IR
0
(4- ~ benzaldehydeethenyl boronic3310,1560,1340,8
acid
methylthiophenyl)pyrido[2,3- 19;MS m/z
359
d]pyrimidine M+H +
91 4-amino-6-(4-methylphenyl)-7-4-phenyl- 2-(4-methylphenyl)-IR
((4-phenyl)phenyl)pyrido[2,3-benzaldehydeethenyl boronic3345,1560,820;M
acid
d]pyrimidine S m/z 389
M+H +
9 4-amino-6-(4-methylphenyl)-7-4-phenylmethoxy-2-(4-methylphenyl)-IR
2
((4' ~~yde ethenyl boronic3400.1340,1245,7
acid
phenylmethoxy)phenyl)pyrido[ 00;MS m/z
419
2,3-d]pyrimidine
M+H +
9 4-amino-6-(4-methylphenyl)-7-4-(N,N- 2-(4-methylphenyl)-IR
3
((4-N,N- diethylamino)-ethenyl boronic3330,1550,1200,8
acid
diethylamino)phenyi)pyrido[2,3benzaldehyde 19;MS m/z
384
-d]pyrimidine M+H +
-39-
SUBSTITUTE SHEET (RULE 26~
CA 02287465 1999-10-14
WO 98/46603 PCT/US98/04127
9 4-amino-6-(4-methylphenyl)-7-4-(2-phenylethenyl)-2-(4-methylphenyl)-IR
4
((4-2- benz.~ldehydeethenyl boronic3460.1600,1340,6
acid
phenylethenyi)phenyl)pyrido[2, 90:MS m/z
41 S
3-d]pyrimidine M+H +
9 4-amino-6-(4-methylphenyl)-7-4-(2-methyl-2-2-(4-methylphenyl)-IR
5
(4-(2-methyl-2- propoxy)- ethenyl boronic3315,1550,1160,9
acid
propoxy)phenyl)pyrido[2,3-benTaldehyde OO;MS mlz
385
d]pyrimidine +
M+H
9 4-amino-6-(4-methyiphenyl)-7-3-chloro- 2-(4-methylphenyl)-IR
6
(3-chiorophenyl)pyrido[2,3-benzaldehyde ethenyl boronic3050,1555,1340,
acid
d]pyrimidine 825:MS m/z
347
M+H +
9 4-amino-6-(4-methylphenyl)-7-3,5-dimethoxy-2-(4-inethylphenyl)-IR 3430,
7 1600,
(3,5- benzaldehyde ethenyl boronic1200, 720;MS
acid m/z
dimethoxyphenyl)pyrido[2,3- 373 (M+H)+.
d idine
98 4-amino-6-(thiophen-2-yl)-7-(4-4-(N,N- 2-(thiophen-2-yl)-IR
3320,1590,
N,N- dimethylamino)-ethenyl boronic700:MS mlz
acid 348
dimethylphenyl)pyrido[2,3-benzaldehyde (M+H)+.
d idine
9 4-amino-6-(4-methylphenyl)-7-benzofuran-2-2-(4-methylphenyl)-IR 3310,
9 1640.
(benzofuran-2-yl)pyrido[2,3-carboxaldehydeethenyl boronic750;MS m/.
acid 353
d]pyrimidine M+H +
100 4-amino-6-(thiophen-2-yl)-7-thiophen-2- 2-(thiophen-2-yl)-IR 3315,
1560,
(thiophen-2-yl)pyrido[2,3-carboxaldehydeethenyl boronic1420, 700;MS
acid nz/z
d]pyrimidine 311 M+H +
101 4-amino-6-(thiophen-2-yl)-7-(4-4-methoxy- 2-(thiophen-2-yl)-1R 3400,
1560,
methoxyphenyl)pyrido[2,3-benzaldehyde ethenyl boronic1250, 835;MS
acid m1z
d]pyrimidine 335 M+H +
102 4-amino-6-(4-bromophenyl)-7-4-(N,N- 2-(4-bromophenyl)-IR 3330,
1545,
(4-N,N- dimethylamino~ethenyl boronic1190, 810;MS
acid mlz
dimethylphenyl)pyrido[2,3-benzaldehyde 420 (M+H)+.
d idine
103 4-amino-6-(3-bromo-4-4-(NN- 2-(3-bromo-4-IIt 3380.
1590,
methoxyphenyl)-7-(4dimethylamino)-methoxy-phenyl)-1200, 820;MS
NN- mlz
dimethylphenyl)-pyrido[2,3-benzaldehyde ethenyl boronic451. (M+H)+.
acid
d idine
104 4-amino-6-(3-bromo-4-thiophen-2- 2-(3-bromo-4-IR 3400.
1550.
methoxy-phenyl)-7-((thiophen-carboxaldehydemethoxy-phenyl)-1280, 715;MS
3- m/z
2-yl)pyrido[2,3-d]pyrimidine ethenyi boronic414 M+H +
acid
10 4-amino-6-(4-methylphenyl)-7-4- 2-(4-methylphenyl)-na
5
(4-butoxyphenyl)pyrido[2,3-butoxybenzaldehydeethenyl boronic
acid
d idine
106 4-amino-6-(4-methylphenyl)-7-3- 2-(4-methyiphenyl)-na
(3-methoxyphenyl)pyrido[2,3-methoxybenzaldehydethenyl boronic
acid
d idine a
10 4-amino-6-(4-methylphenyl)-7-3,5-dichloro-2-(4-methylphenyl)-na
7
(3.5-dichlorophenyl)pyrido[2,3-benzaldehyde ethenyl boronic
acid
d idine
-40-
SUBSTITUTE SHEET (RULE 26)
